UA75572C2 - Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of diabetic retinopathy - Google Patents

Abstract

, (I) , (II) , (III) , (IV) The present invention is directed to a method for the prophylactic and therapeutic treatment of diabetic retinopathy. The method involves the administration of an inhibitor of formulae (I), (II) and (III) of the branch chain amino acid-dependent amino-transferase (BCAT) pathway to an animal, such as a mammal, in particular a human, in an amount sufficient to treat the retina for diabetic retinopathy prophylactically or therapeutically. The present invention is also directed to several novel inhibitors of formula (IV) of the BCAT pathway. In formulae (I-IV), n, m, X and R1-R13 have the meanings given in the description.

Description

Description of the invention

More than 14 million people in the United States have diabetes. All patients with diabetes are in the 2nd risk group with retinal complications. However, patients with type I diabetes, i.e. insulin-dependent diabetes, are at a much greater risk of vision loss than patients with type II diabetes, i.e. non-insulin-dependent diabetes.

Any non-inflammatory disease of the retina is called retinopathy. Diabetic retinopathy is any retinopathy associated with any form of diabetes.

Initially, a high level of glucose in the blood of diabetic patients causes an increase in the activity of growth factors 70 in their eyes. This condition is known as "pre-diabetic retinopathy" It can lead to full diabetic retinopathy in the absence of preventive treatment.

Retinopathy affects most diabetic patients almost throughout their lives. It is now the leading cause of blindness in Americans between the ages of 20 and 74, and approximately one-third of diabetics in the United States suffer from vision impairment. Up to 40,000 72 new cases of blindness occur annually in the United States among patients with diabetes (SOS, unpublished data, 1993). People with diabetes are 25 times more likely to go blind from retinopathy than the general population.

The course of diabetic retinopathy includes a two-stage non-proliferative stage, which usually occurs first, and a proliferative stage. The nonproliferative stage, also known as "background diabetic retinopathy", is characterized by thickening of the basement membrane, loss of retinal pericytes, disturbances in capillaries, intraretinal aneurysms, retinal hemorrhages (also known as "spotted" hemorrhages), retinal edema, in particular, diabetic macular edema, occlusion capillaries associated with retinal ischemia or poor retinal perfusion (ie, poor vascular development) and soft or hard exudates. The proliferative stage, covering approximately 700,000 Americans |(Spep ei ai.,.). Mivv.

Ziaie May. Avzvos 36(7): 201-208 (1995)), characterized by neovascular processes and fibrovascular growth (i.e., scarring involving glial and fibrous elements) from the retina or optic nerve through the inner surface of the retina or disc or into the vitreous cavity .

The proliferative stage can lead to cortical or neovascular glaucoma. Macular edema can occur at any stage and, along with complications related to neovascular processes in the retina, they are the two main retinal problems causing vision loss associated with diabetes. with

Although the pathological stages of diabetic retinopathy are well described, the molecular mechanisms underlying it are not fully understood. This is partly due to the fact that the disease develops over 10-30 years, depending on personal characteristics. at

Strict control of glycemia and hypertension and ophthalmological observation of patients with diabetes give good results in preventing the disease. Modern methods of treatment include observation by an ophthalmologist, laser 3o photocoagulation and excision of the vitreous body. in

The threat of macular edema or damage to the macular center is treated with focal macular photocoagulation. These are small (50 millimicron in diameter) low-intensity laser cauterizations in areas of leakage on the macula (Mygrpu, Ateg. Ratiyu RNuzisiap 51 (4): 785-796 (1995)). If macular edema occurs again, retreatment may be necessary. Of 50 Patients with intense and very intense nonproliferative retinopathy and patients at high risk of proliferative retinopathy or with early or advanced proliferative retinopathy are treated with

From" scattered or panretinal photocoagulation. Panretinal photocoagulation involves 1,500-2,000 laser cauterizations, each about 500 millimicrons in diameter, in the midperipheral or peripheral part of the retina (Mygrpu (1995), see above).

The best described biochemical mechanism of development of microvascular complications and Compounds of Formula B: 1 - 5 aka

Co.); ii and DAH NIA pedezitniv them

Nanospring-ebony and: ! I

F) with ka Wu. 60 or their pharmaceutically acceptable salts, where K 1 means a linear or branched alkyl group with the number of carbon atoms from 1 to 6, phenyl or cycloalkyl with the number of carbon atoms from C to 6; Co stands for hydrogen or methyl; Kz means hydrogen or carboxyl, known (under US Pat. No. 5,563,175) and patents issued therefrom.

These patents are incorporated herein by reference.

The present invention also relates to new compounds of Formula IM b5

In the "p nan 70 sh

You - - t. MAR. what else SHY a. She Y a

Where is she?

K.-K. is hydrogen or alkyl; c 29 X means MK" or 0; Go)

K"5 means hydrogen or alkyl,

Ke means hydrogen, alkyl, benzyl, alkanoyl, alkoxyalkanoyl, arylalkyl, alkoxy group, cycloalkyl, allyl, alkylcycloalkyl, trisubstituted haloalkyl, and if K.-K. each is hydrogen, then K; is not hydrogen or methyl; ch or its pharmaceutically acceptable salt, ester, prodrug or amide. Like the compounds of Formulas I, III and PS, these compounds are applicable for the prophylactic and therapeutic treatment of diabetic retinopathy, including the treatment of - the preliminary stage of diabetic retinopathy, the non-proliferative stage of diabetic retinopathy, and the proliferative stage of diabetic retinopathy.

Those compounds of Formula IM are preferred, where K» and Ku are hydrogen, and Ku and Kz are alkyl; Ko and Kk; is hydrogen, and Ki. and Kz is M methyl; K.-K. is hydrogen; K. is alkyl, and Co-K. is hydrogen; Ki is methyl and Co is K; is hydrogen; K5 is hydrogen; X is m

MKa; X is O; Ke is alkyl; Co.; is benzyl; Co.; is acetyl; K; is phenylalkyl; Co is cycloalkyl; Ke is trifluoroalkyl; Ke is alkylcycloalkyl; Ke is an alkoxy group and Co is allyl.

Other preferred compounds of Formula IM are those where K" and Ku. is hydrogen, and K. and Kz are methyl; K.--Ka is hydrogen; K.4 is methyl, and Co-K. is hydrogen; K5 is hydrogen; X is MKe; Ke is alkyl; Ke is benzyl; Co is acetyl; Ke is "di phenylalkyl; Co is cycloalkyl; Ke is trifluoroalkyl; Co is alkylcycloalkyl; Ka is an alkoxy group and Ke is an allyl group. c Particularly preferred compounds are selected from the list: :c» (1-Allylaminomethyl-cyclohexyl)-acetic acid; (1-Prop-2-inylaminomethyl-cyclohexyl)-acetic acid; 15 (112 2,2-Trifluoroethylamino)-methyl|-cyclohexyl) acetic acid; - 11-K3,3,39-Trifluoropropylamino)-methyl|-cyclohexyl)-acetic acid; 1A,38,58-(1-Allylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid; 1 1A,38,58-(3,5-Dimethyl-1-prop-2-inilaminomethyl-cyclohexyl)-acetic acid; cl 1A,38,58-13,5-Dimethyl-1-((2,2,2-trifluoro-ethylamino)-methyl|-cyclohexyl)-acetic acid; 1A,38,58-13,5-Dimethyl-1-((3,3,3-trifluoro-propylamino)-methyl|-cyclohexyl)-acetic acid; -and 20 diabetes is the metabolic pathway of sorbitol. In the sorbitol metabolic pathway, the aldose reductase enzyme catalyzes the conversion of glucose into sorbitol and galactose into galactite. Aldose reductase has low substrate specificity for glucose. Therefore, when the glucose concentration is normal, this metabolic pathway is inactive. In hyperglycemia, it becomes active. Activation of the sorbitol metabolic pathway important, for example, to retinal pericytes, which do not require insulin to absorb glucose. Also, retinal capillary cells show significant amounts of aldose reductase (Gregitiz, Nozria!| Rgasiise: 79-89 (Mau 15, 1993).

GF) Taking into account the prevalence of diabetic retinopathy, the need for effective 7 preventive and therapeutic treatment of this disease becomes obvious. Therefore, the main object of this invention is a method of prophylactic and therapeutic treatment of diabetic retinopathy, including the treatment of the previous stage of diabetic retinopathy, the non-proliferative stage of diabetic retinopathy, and the proliferative stage of diabetic retinopathy. This and other objects of the present invention will become apparent from the detailed description below.

The present invention relates to a method of prophylactic and therapeutic treatment of diabetic retinopathy, including the treatment of the previous stage of diabetic retinopathy, the non-proliferative stage of diabetic retinopathy, and the proliferative stage of diabetic retinopathy. The method includes the appointment of an inhibitor of 65 metabolic pathways controlled by aminotransferases dependent on branched chain amino acids. Preferably, the inhibitor of metabolic pathways controlled by aminotransferases dependent on branched chain amino acids (BCAT) is a compound of formulas I, I! and/or PI: ! and

Order

I and t shchi Z, oi lk Sho "I in m, 8 (t " ZHE V, , B.V, y | i - What Z "I You and - Re "

Cedar: I chn, on Z o ' still. about -I 50

From 52 iF) ime) 60 b5

THOSE

70 Pika SHK Z san

Zhet and ro. Y. m ny A U She p 20 KI v e Va Ko de: cm 29 Ko is NN; alkyl; cycloalkyl; substituted alkyl containing a halogen, amine, alkoxy group, Ho) cycloalkyl or hydroxyl; allyl; alkynyl; alkanoyl; Alkoxyalkanoyl; sulfonyl; phenyl; benzyl or aralkyl; t and n are independent integers from 1 to 3; ch zo K.-Kav and K/0o-K4a4 are independently H, alkyl or substituted alkyl; and

HEMAK 4, O or 5 or its pharmaceutically acceptable salt, ether, prodrug or amide. oh

This compound can have one or more asymmetric carbon atoms and each of the centers of asymmetry can be racemic (K and 5) or chiral (K or 5). IF)

The best compounds of formulas I, II or CI are those where those n are 1; X is MK.4; Ko is H; EC. is methyl; K, and K5 is methyl; Ka m 35 is methyl; Co is methyl; K» and Ka are methyl; K, and Ka is methyl; K.-Ka and Kl0-K4z are H; K" is alkyl; Co is benzyl;

Ki4 is alkyl; Ko is aralkil; Co is cycloalkyl; K4-Ka is H; K1-Ka and K/o-Kch41 are H; K.-K»o and K,-Ka are H or Ko» is methyl.

More preferred compounds are the compounds of formula II, where Kz is alkyl, K.-K»o and KA-K44 and K-4 are hydrogen, such as those, and "du X is MKCh4; Kz and K.4 are alkyl, K.4-K»o and KA-Kcho and K/4 are hydrogen, t and n are 1, and X is MK.4; Kz and K.44 are alkyl, K.4-K» and KA-Kio are hydrogen, those n are 1, and X is MK.4; Kz and K44 are alkyl, K.4-K» and KA-Kuo and Ki4 are hydrogen, those n are 1, Ko is alkyl, and X is s ME cha; and K./-K.4 and K44 are hydrogen, tipe tah is o. Especially preferred compounds are selected from: (1-Allylaminomethyl-cyclohexyl)-acetic acid; (1-Prop-2-inylaminomethyl-cyclohexyl)-acetic acid; 11-K2,2,2-Trifluoroethylamino)-methyl|-cyclohexyl)-acetic acid; - and in I 11-K3,3,39-Trifluoro-propylamino)-methyl|-cyclohexyl)-acetic acid; 1 1А,38,58-(1-Allylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid; cl 1A,38,58-(3,5-Dimethyl-1-prop-2-inilaminomethyl-cyclohexyl)-acetic acid; 1A,38,58-13,5-Dimethyl-1-((2,2,2-trifluoro-ethylamino)-methyl|-cyclohexyl)-acetic acid; - and 20 1A,38,58-13,5-Dimethyl-1-((3,3,3-trifluoro-propylamino)-methyl|-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-Allylaminomethyl-3-methyl-cyclohexyl)-acetic acid;

Ko) p. . trans-(1k,ZK)-3-Methyl-1-prop-2-inylaminomethyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-3-Methyl-1-((2,2,2-trifluoro-ethylamino)-methyl|-cyclohexyl)-acetic acid; trans-(1k,ZK)-3-Methyl-1-((3,3,3-trifluoro-propylamino)-methyl|-cyclohexyl)-acetic acid; 59 transo-C1K,3Kk)-3-Methyl-1-(4,4,4-trifluoro-butylamino)-methyl|-cyclohexyl)-acetic acid;

HF) 1A,38B,58-13,5-Dimethyl-1-(4,4,4-trifluoro-butylamino)-methyl|-cyclohexyl)-acetic acid;

ГФ 1А,38,58-(1-(Cyclopropylmethyl-amino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-(Cyclopropylmethyl-amino)-methyl|-3-methyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-3-Methyl-1-methylaminomethyl-cyclohexyl)-acetic acid; 60 and trans-(1Kk,3K)-1-Ethylaminomethyl-33-methyl-cyclohexyl)-acetic acid; trans-(1kK,3K)-3-Methyl-1-propylaminomethyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-Butylaminomethyl-3-methyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-Hydroxymethyl-3-methyl-cyclohexyl)-acetic acid; 1A,38,58-11-K(Hydoxymethyl-amino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid; bo 1A,38,58-(1-Aminomethyl-3,5-diethyl-cyclohexyl)-acetic acid hydrochloride;

trans-(1Kk,ZKI(1-Aminomethyl-3-methyl-cyclohexyl)-acetic acid hydrochloride; (1-Aminomethyl-2-methyl-cyclohexyl)-acetic acid hydrochloride; (1-Aminomethyl-3,3-dimethyl-cyclohexyl )-acetic acid hydrochloride; (1--) (trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride; (cis/trans)-(3K)-(1-Aminomethyl-3- methyl-cyclopentyl)-acetic acid hydrochloride; (U (trans)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride; (U (trans)-(1-Aminomethyl-3,4-dimethyl- cyclopentyl)-acetic acid hydrochloride; 1A,38,58-(1-Aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; 70 1A,38,58-(3,5-Dimethyl-1-propylaminomethyl-cyclohexyl) )-acetic acid hydrochloride; 1A,38,58-(1-Ethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; 1A,38,58-((1-Benzylamino-methyl)-3,5-dimethyl -cyclohexyl|-acetic acid hydrochloride; 1A,38,58-(1-Dimethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; 1A,38,58-(1-Butylaminomethyl-3,5-dimethyl-cyclohexyl) )-oc tonic acid hydrochloride; 1A,38,58-11-(Benzyl-methyl-amino)-methyl)|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; 1A,38,58-(3,5-Dimethyl-1-methylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 1A,38,58-11--Acetylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid; 1A,ZB,58-|1-(Isobutylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid hydrochloride; 1A,38,58-I3,5-Dimethyl-1-(phenethylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; 1A,38,58-13,5-Dimethyl-1-((3-phenyl-propylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(Cyclobutylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 1A,38,58-(11-(Isopropylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid hydrochloride; 1-Aminomethyl-1-cyclohexane-acetic acid; 1-Aminomethyl-1-cyclopentane-acetic acid; 1-Aminomethyl-1-cyclopentane-acetic acid sodium salt; 1-"Hydroxymethyl)cyclohexane-acetic acid sodium salt; i) 11-(2-Methyl-butylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(4,4,4-Trifluoro-butylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-Eethylaminomethyl-cyclohexyl)-acetic acid hydrochloride; c zo 11-Cyclopropylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-K2-Hydroxy-1-methyl-ethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; - (1-(Isobutylamino-methyl|-cyclohexyl|-acetic acid hydrochloride; y (1-Propylaminomethyl-cyclohexyl)-acetic acid hydrochloride; (1-(Isopropylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; o (1- Cyclohexylaminomethyl-cyclohexyl|-acetic acid hydrochloride; 1-(1-(Benzylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; (1K,3K)-3-Methyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 11- (Cyclopentylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(Cyclohexylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride;

P1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl|-acetic acid; with c (1-"-Acetylamino-methyl)-cyclohexyl|- acetic acid; (3K,55)-1-Cyclobutylaminomethyl)-3,5-dimethyl-cyclohexyl-acetic acid hydrochloride; ;" u3kK,55)-3,5-Dimethyl-1-(2-methyl-butylamino)-methyl)|-cyclohexyl)-acetic acid hydrochloride;

T(3K,55)-1-K(2-Hydroxy-1-methyl-ethylamino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride;

T(3K,55)-1-(2,2-Dimethoxy-ethylamino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; -I T(3K,55)-1-"Cyclopentylmethyl-amino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; -(ZK,55)-1-(Cyclohexylmethyl-amino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; o (ZK,55)-1-Cyclohexylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; c (3K,55)-1-Carboxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid; trans-((ZK,55)-1-Hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride;

X-cis-(ZK,55)-1-Hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride;

Ge (1-Dimethylaminomethyl-cyclohexyl)-acetic acid hydrochloride; (1-Butylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 11-(2,2-Dimethoxy-ethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-Methylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 11-Kbenzyl-methyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride;

F) (1-Kphenethylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; ka 11-KZ-Phenyl-propylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-Hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid sodium salt; in (ZK,55)-1-Ethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; (1-Aminomethyl-4-ethyl-cyclohexyl)-acetic acid hydrochloride; (1-Aminomethyl-4-propyl-cyclohexyl)-acetic acid hydrochloride; (Z3K,55)-3,5-Dimethyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride;

I 1K,ZK)-1-(Benzylamino-methyl)-3-methyl-cyclohexyl|-acetic acid hydrochloride; 65 XIkK,3Kk)-1-(Benzyl-methyl-amino)-methyl|-33-methyl-cyclohexyl)-acetic acid hydrochloride; or

(1K,3K)-3-Methyl-1-methylaminomethyl-cyclohexyl)-acetic acid hydrochloride;

Several compounds described by the formulas I, ІІ and ІІ are known. Compounds of Formula A:

And then (Na

A. 12 where Ku is hydrogen or a lower alkyl radical, and n means 4, 5 or 6, known |from US Patent Mo4024175)| and extracted from it |US Patent Mo4087544). The compounds described there have the following qualities: protective effect against spasms caused by thiosemicarbazide, protective effect against cardiozole spasms, cerebral diseases, epilepsy, attacks of weakness, hypokinesia and cranial injuries, improvement of cerebral functions. These compounds are useful for geriatric patients. Said patents are incorporated herein by reference. trans-(1Kk,3K)-1-Allylaminomethyl-3-methyl-cyclohexyl)-acetic acid; trans-(1k,ZK)-3-Methyl-1-prop-2-inylaminomethyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-3-Methyl-1-((2,2,2-trifluoro-ethylamino)-methyl|-cyclohexyl)-acetic acid; trans-(1k,ZK)-3-Methyl-1-((3,3,3-trifluoro-propylamino)-methyl|-cyclohexyl)-acetic acid; trans-C1K,3Kk)-3-Methyl-1-(4,4,4-trifluoro-butylamino)-methyl|-cyclohexyl)-acetic acid; ch 29 1A,38,58-13,5-Dimethyl-1-(44,4-trifluoro-butylamino)-methyl|-cyclohexyl)-acetic acid; Ge) 1A,38,58-(1-(Cyclopropylmethyl-amino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-(Cyclopropylmethyl-amino)-methyl|-3-methyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-3-Methyl-1-methylaminomethyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-Ethylaminomethyl-33-methyl-cyclohexyl)-acetic acid; c 30 trans-(1kK,3K)-3-Methyl-1-propylaminomethyl-cyclohexyl)-acetic acid; h- trans-(1Kk,3K)-1-Butylaminomethyl-3-methyl-cyclohexyl)-acetic acid; trans-(1Kk,3K)-1-Hydroxymethyl-3-methyl-cyclohexyl)-acetic acid; 1A,38,58-11-KHydroxymethyl-amino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid; 1A,38,58-(1-Aminomethyl-3,5-diethyl-cyclohexyl)-acetic acid hydrochloride; 35 1A,38,58-(3,5-Dimethyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride; - 1A,38,58-(1-Ethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; 1A,38,58-((1-Benzylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid hydrochloride; 1A,38,58-(1-Dimethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; « 1A,38,58-(1-Butylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; t0 1A,38,58-11-(Benzyl-methyl-amino)-methyl)|-3, 5-dimethyl-cyclohexyl)-acetic acid hydrochloride; 8 s 1A,38,58-(3,5-Dimethyl-1-methylaminomethyl-cyclohexyl)-acetic acid hydrochloride; "from 1A,38,58-(11-«-Acetylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid; 1A,3B,58-|I1-(Isobutylamino-methyl)-3,5-dimethyl -cyclohexyl|-acetic acid hydrochloride; 1A,38,58-13,5-Dimethyl-1-(phenethylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; 45 1A,38,58-13,5-Dimethyl-1- ((3-phenyl-propylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(Cyclobutylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; c 1A,38,58-(11-(Isopropylamino- methyl)-3,5-dimethyl-cyclohexyl|-acetic acid hydrochloride; 11-(2-Methyl-butylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; and 11-(4,4,4-Trifluoro- butylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; -I 20 (1-Eethylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 11-Kcyclopropylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-K2 -Hydroxy-1-methyl-ethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-(Isobutylamino-methyl|-cyclohexyl|-acetic acid hydrochloride; (1-Propylaminomethyl-cyclo Ohexyl)-acetic acid hydrochloride; (1-(Isopropylamino-methyl)-cyclohexyl|-acetic acid hydrochloride;

HF) (1-Cyclohexylaminomethyl-cyclohexyl|-acetic acid hydrochloride; (1-(Benzylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; co pam ; : (1K,3K)-3-Methyl-1-propylaminomethyl-cyclohexyl )-acetic acid hydrochloride; 11-(Cyclopentylmethyl-amino)-methyl-cyclohexyl)-acetic acid hydrochloride; 60 11-(Cyclohexylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride;

P1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl|-acetic acid; (1-"-Acetylamino-methyl)-cyclohexyl|-acetic acid; (3K,55)-1-Cyclobutylaminomethyl)-3,5-dimethyl-cyclohexyl-acetic acid hydrochloride; y3K,55)-3,5-Dimethyl-1-(2-methyl-butylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; bo T(3K,55)-1-K(2-Hydroxy-1-methyl-ethylamino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride;

T(3K,55)-1-(2,2-Dimethoxy-ethylamino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride;

T(3K,55)-1-cyclopentylmethyl-amino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride;

T(3K,55)-1-(Cyclohexylmethyl-amino)-methyl/|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-Cyclohexylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; (3K,55)-1-Carboxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid; trans-((ZK,55)-1-Hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; cis-(ZK,55)-1-Hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; (1-Dimethylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 70 (1-Butylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 11-(2,2-Dimethoxy-ethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-Methylaminomethyl-cyclohexyl)-acetic acid hydrochloride; 11-Kbenzyl-methyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-Kphenethylamino-methyl)-cyclohexyl|-acetic acid hydrochloride; 11-KZ-Phenyl-propyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-Hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid sodium salt; (ZK,55)-1-Ethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride; (1-Aminomethyl-4-ethyl-cyclohexyl)-acetic acid hydrochloride; (1-Aminomethyl-4-propyl-cyclohexyl)-acetic acid hydrochloride; (Z3K,55)-3,5-Dimethyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride;

I 1K,ZK)-1-(Benzylamino-methyl)-3-methyl-cyclohexyl|-acetic acid hydrochloride;

XikK,3Kk)-1-(Benzyl-methyl-amino)-methyl|-33-methyl-cyclohexyl)-acetic acid hydrochloride; and (1K,3K)-3-Methyl-1-methylaminomethyl-cyclohexyl)-acetic acid hydrochloride; high school

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of Formula IM and a pharmaceutically acceptable carrier. and)

Compounds of Formula I such as gabapentin are useful in the treatment of various conditions such as neurodegenerative disorders (5 5084479), depression (05 5025035), anxiety/panic disorder (5 57927961), mania/bipolar disorders (05 55103811), anti-inflammatory diseases (MUO 98 158641), gastrointestinal disorders s zo YIMO 99 108670), glaucoma and pain.Since the compounds of Formula II and Formula IM act through effects on the metabolic pathways of BSAT and glutamate synthesis involved in all of the conditions mentioned above, the compounds of Formula IM are also applicable for - treatment of these conditions Thus, this compound also relates to the use of compounds of Formula IM for the treatment of each or more than one neurodegenerative disorder (including, but not limited to, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease), depression, anxiety/panic disorder o C5 condition, mania/bipolar disorders, anti-inflammatory diseases, glaucoma, pain or gastrointestinal disorders.

Fig.1. Diagram showing the circulation of BSAT in the retina. Normal pathways have been identified that show how branched-chain amino acids in glia can transaminate A-ketoglutarate to form glutamate.

The VSKA product diffuses through the interstitium (shown in gray) to the neurons, where it is again converted to a branched-chain amino acid by transamination with glutamate by BSATe. Abbreviations c are as follows: BCAA - amino acid with a branched chain; SI Sh - glutamate, SI M - glutamine; SI M'avze - glutamine; rug - pyruvate; RS - pyruvate carboxylase; AKO - sso-ketoglutarate; BSATt - mitochondrial BSAT; VSATs - ;" cytosolic BSAT; VSKA - keto acid with a branched chain; OH -glutamate dehydrogenase.

Fig. 2. The effect of pyruvate concentration on the incorporation of H "CO into total glutamate/glutamine (A) and total pyruvate/lactate (B) in the ex mimo retina. The hemi-retinal preparation was incubated at 372 under standard conditions with 25 mM - and H"CO3 for 20 minutes. Pyruvate in the medium was either 0.2 or 5 mm. Mean values with sl taken into account (h/-) standard error of the mean (SPS, n-4, "p "0.05)3 are indicated. Abbreviations: dipndiS means total labeled glutamine/glutamate; rugniasi means total labeled pyruvate/lactate. 1 Fig. 3 . Expression of BSAT isozymes in the rat retina. Extraction from tissue, electrophoresis in -1 50 5ХО5B-polyacrylamide gel (ZO5-PAAG) and immunoblotting were performed as described using an ESI detection kit. Immunoaffinity purified rat anti-BSAT peptide antibodies were used (1 :1000) and

Ko) human anti-VSATTt antibodies (1:1000).

Fig. 4. Effects of gabapentin (GBP) and branched-chain amino acids on the incorporation of H "CO5 into glutamate/glutamine in ex mimo retinas. Half of the retina was incubated at 372C under standard conditions with 25 mM H'""CO" with 22 102 mM pyruvate for 20 minutes. In some cases, gabapentin (1 mM) was included in the incubation medium, in other PIs - GBP (1 mM) and all three branched amino acids at 0.2 mM of each. -4, "p"0.001, ""p"0.01). Abbreviations: dipcode means total labeled glutamine/glutamate.

Fig. 5. The influence of the concentration of gabapentin (GBP) on the inclusion of H "7СО3 in glutamate and glutamine in the retina ex 60 mimo. The conditions are similar to those described in Fig. 4, except for the concentration of GBP. The average values of 47/-SPS (p-6-7, " p«0.05). Abbreviations: BI MS means total glutamine/glutamate; (ASTATSA means the total value of lactate and intermediates of the TSA cycle.

The present invention is based on the observation that intraocular injection of glutamate causes the loss of ganglion cells, which usually occurs in the early stages of diabetic retinopathy (Mohmegk et al. (05 37:1618-1624 bo (1996))) and that an inhibitor of the metabolic pathway of aminotransferases, branched-chain amino acid-dependent agents such as gabapentin effectively inhibit glutamate synthesis, thereby preventing diabetic retinopathy.Accordingly, the present invention relates to a method of prophylactic and therapeutic treatment of diabetic retinopathy, including treatment of pre-stage diabetic retinopathy, non-proliferative stage of diabetic retinopathy and the proliferative stage of diabetic retinopathy. By "prophylactic" treatment is meant the protection in whole or in part of diabetic retinopathy, especially from diabetic macular edema. By "therapeutic" treatment is meant the overcoming of the effects of diabetic retinopathy itself and the protection of all or part of the cellulium from further development of diabetic retinopathy, in particular, from macular diabetic edema. 70 The method includes the appointment of an inhibitor of aminotransferase metabolic pathways dependent on branched chain amino acids, in an amount sufficient to treat the retina from retinopathy prophylactically or therapeutically. Any inhibitor of aminotransferase metabolic pathways dependent on branched chain amino acids can be used in the method of this invention, as long as it is safe and effective.

Here, the term "branched-chain amino acid-dependent aminotransferase (BCA) inhibitor" 7/5 is used in relation to such compounds and includes all compounds that act on the branched-chain amino acid-dependent aminotransferase metabolic pathways at any and all points metabolic pathway.

Preferably, the BSAT inhibitor is a compound of Formulas I, II and I, as described above, or pharmaceutically acceptable analogs that inhibit the metabolic pathways of BSAT, or prodrugs thereof, or their fpharmaceutically acceptable salts, 2o esters, or amides of each.

Unless otherwise noted, the following definitions apply throughout the text of the description. "Alkyl" means a straight or branched hydrocarbon radical containing from 1 to 10 carbon atoms (unless specifically discussed) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -pentyl, iso-pentyl, n-hexyl, and the like. "Halogen" means fluorine, chlorine, bromine and iodine. "Alkenyl" means a linear or branched hydrocarbon radical containing from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl and others like them. "Alkynyl" means a linear or branched hydrocarbon radical containing from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyne -1-il and the like. "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl.

Such groups can be replaced by hydroxyl, keto group and the like. The term also includes rings in which from 1 to 3 heteroatoms replace carbon atoms. Such groups are called "heterocyclyls", which are cycloalkyl groups bearing at least one heteroatom selected from O, 5 or MK", examples of which are substituted or unsubstituted oxyranyl, pyrrolidinyl, piperidyl, tetrahydrofuran, piperazinyl, acylpiperazinyl, y-pyrrolidinyl and morpholine. "Alkoxy group" refers to the alkyl groups mentioned above linked through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy and the like. In addition, the term alkoxy group refers to polyesters such as -O-(СНо)»-О-СНу» and the like. "Alkanoyl" is an alkyl linked through a carbonyl, i.e. C 5-C5-C(O)-. Such groups include formyl, pt) with acetyl, propionyl, butyryl and isobutyryl. "Acyl" is an alkyl or aryl (Ag) group connected through a carbonyl, i.e. K-C(O)-. For example, acyl includes alkanoyl having from 1 to b carbon atoms, including substituted alkanoyl, where the alkyl moiety may be substituted by ME" or a carboxyl or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like. -I Alkyl, alkenyl , alkoxy- and alkynyl groups described above can be optionally substituted by preferably 1-3 groups selected from the group consisting of ME"B?, phenyl, substituted phenyl, thioalkyl with the number of carbon atoms from 1 to 6, alkyl - a group with the number of carbon atoms from 1 to 6, hydroxyl, carboxyl, 1-alkoxycarbonyl with the number of carbon atoms from 1 to 6, halo group, nitrile, cycloalkyl, and 5- or b-lene - 50 carbocyclic ring or heterocyclic ring, containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur. that) "Substituted nitrogen" means a nitrogen bearing an alkyl having from 1 to 6 carbon atoms or (CHO) RI, where n is 1, 2 or 3. Perhalo or polyhalo substitutions are also included.

Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl,

3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinepropyl, o-piperazinylmethyl and 2-(4-methylpiperazinyl)ethyl. ime) Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanylethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3 -butynyl, 60 4-cyclobutyl-4-hexenyl and the like.

Typical substituted alkoxy groups include aminomethoxy group, trifluoromethoxy group, 2-diethylaminoethoxy group, 2-ethoxycarbonylethoxy group, 3-hydroxypropoxy group, b-carboxyhexyloxy group, and the like.

Additionally, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, 65 carboxymethyl, 4-dimethylamino-3-buten-1-yl, B-ethylmethylamino-3-pentyn-1-yl, 4-morpholinebutyl, 4-tetrahydropyridinylbutyl, C -imidazolin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,

C-chlorophenylmethyl and the like.

The terms "aryl" and "Ag" refer to unsubstituted and substituted aromatic groups. Heteroaryl groups contain from 4 to 9 ring atoms, from 17 to 4 of which are independently selected from the list that includes O, 5 and M. Preferred heteroaryl groups contain 1 or 2 heteroatoms in a 5- or b--ene aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4, 7-dichloronaphthyl, pyrrole, pyrazole, imidazole, thiazole and the like. 70 The best Ar-groups are phenyl and phenyl substituted with 1, 2 or C groups, independently selected from the list, which includes an alkyl, an alkoxy group, a thio group, a thioalkyl, a hydroxyl, a carbonyl, an amino group of the formula -ME"B? and so on (СНо)тОВy or Т(СНо)тСО»вБ, where t means from 1 to 6, T means O, 5, MA", MOV", ME7В5 or SEР», O means O, 5,

MA5 MOZ or MAV where B" and KZ are defined as above, and B / means alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl and the like. Alkyl and alkoxy groups can be substituted as defined 72 above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkyl, and alkoxyalkyl.

The symbol "-" means a connection.

The term "patient" means all animals, including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.

The compounds of this invention can exist in unsolvated forms as well as in solvated forms, including hydrated form. In general, the solvated forms, including the hydrated form, are equivalent to the unsolvated forms and are within the scope of the present invention.

Certain compounds of this invention contain one or more chiral centers, and each center can exist in the K (0) or 5 (I) configuration. This invention includes all enantiomeric and epimeric forms, as well as their mixtures. with

Compounds of Formulas I, II and X are capable of further formation of both pharmaceutically acceptable analogues, which include salts, ethers, amides, and prodrugs. In this description, the term "pharmaceutically acceptable salts, esters, amides and prodrugs" refers to those carboxylate salts, salts of amino acid compounds, esters, amides and prodrugs of the compounds of this invention, which, within the limits of medically known data, are applicable for use in contact with patient tissues , having no undesirable toxic, irritating or allergic effects and similar effects, meet the required ratio of benefits and risks and are effective in their use, as well as, when possible, zwitterionic forms of the compounds of this invention. The term "salts" refers to relatively non-toxic inorganic and organic salts of the compounds of this invention. These salts can be obtained i.e. during the final isolation and it) purification of compounds or during separate reactions of purified compounds in their free base form with appropriate organic or inorganic acids with subsequent purification, and include, but are not limited to, salts of compounds of acids and /or basic salts, solvents and M-oxides of compounds of Formulas I, II and X. This invention also includes (- Its pharmaceutical formulations comprising compounds of Formulas I, II or I together with a pharmaceutically acceptable carrier, diluent or excipient. All these forms are encompassed within the scope of this invention.

Pharmaceutically acceptable salts of compounds of acids of compounds of Formulas I, II and IP include salts of inorganic salts, such as salt, nitrogen, phosphoric, sulfuric, hydrogen bromide. hydrogen iodide, phosphoric acid, and the like, as well as salts of organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic C c acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic "» sulfonic acids, etc. Such salts, respectively, include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, and phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, tartrates, methanesulfonates and the like. Amino acid salts, such as arginates, gluconates, galacturonates and the like, are also considered.

See, for example, Begode, ei ai., "Rpagtaseciisa! Zai(8", 9. oi Rpagtaseciisa! Zsiepse, 1977; 66:1-19). o Salts of compounds of acids of basic compounds are obtained by conducting a reaction of the free base form with -1 50 a sufficient amount of the desired acid to obtain a salt by a known method. The free base form can be regenerated by reacting the salt form with the base and releasing the known free base

IR) method. The free base form sometimes differs from the corresponding salt form in some physical properties, such as solubility in polar solvents, but if not, such salts are equivalent to their corresponding free base forms for the purposes of this invention. 29 Pharmaceutically acceptable salts of base compounds are formed with metals or amines, such as hydroxides of alkali or alkaline earth metals, or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of applicable amines are M,M'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, M-methylglucamine and procaine, see e.g. , Vegode ei aiYi. above. because the salts of compounds of the bases of acidic compounds are obtained by reacting the free acid form with a sufficient amount of the desired base to obtain a salt by a known method. The free acid form can be regenerated by reacting the salt form with an acid and releasing the free acid in a known manner. The free acid form sometimes differs from the corresponding salt form in certain physical properties, such as solubility in polar solvents, but if not, such salts are equivalent to their corresponding free acid forms for the purposes of this invention.

Examples of pharmaceutically acceptable non-toxic esters of the compounds of this invention include alkyl ethers having 1 to 6 carbon atoms, where the alkyl group is a linear or branched chain. Acceptable ethers also include cycloalkyl ethers having 5 to 7 carbon atoms, as well as arylalkyl ethers such as, but not limited to, benzyl. Alkyl ethers with the number of carbon atoms from 1 to 4 are preferred. The esters of the compounds of this invention can be obtained according to known methods.

Examples of pharmaceutically acceptable non-toxic amides of the compounds of this invention include amides derived from ammonia, primary alkyl amines having 1 to 6 carbon atoms, and secondary dialkyl amines having 1 to 6 carbon atoms where the alkyl groups are linear or branched chain. In the case of secondary amines, the amines can also be in the form of a 5- or b-membered heterocycle containing 1 nitrogen atom. 70 Amides derived from ammonia, primary alkyl amines with a number of carbon atoms from 71 to 3, and dialkyl secondary amines with a number of carbon atoms from 1 to 2 are preferred. Amides of the compounds of this invention can be obtained by known methods.

The term "prodrugs" refers to compounds that are rapidly transformed into a product corresponding to the Formulas mentioned above, for example, by hydrolysis in the blood. A detailed discussion of the problem can be found in T. 7/5 Nidispi apa M. zieMa, "Rgo-dgyd5 az pome! Oeiiimegu Zuzietv", Mo! 14 of A.S.5. Zitrozit Zegie5, as well as in

Viohemegvirie Sagiegz ip Ogyd YuOevidp, ey. ru Eidmjaga V. Kospe, Ategisap RNaptaseshiisa! Avvzosiaiop apa

Regdatop Rgezv, 1987)|), both sources are included in this description as a reference. In general, prodrugs are drugs that have been chemically modified and may be biologically inactive at the site of action, but which may be degraded or modified by one or more enzymatic or other processes into the parent bioactive form.

A therapeutically effective amount is the amount of a compound of Formula I, II or I that, when administered to a patient, has a positive effect on the symptoms of the disease.

A BSAT inhibitor, which is preferably a compound of Formulas I, II and/or I, which inhibit the metabolic pathways of BSAT, analogs of compounds of Formulas I, II (or Ш, which inhibit the metabolic pathways of BSAT, prodrugs of compounds of Formula | Acceptable salts of each of the above embodiments may be administered in accordance with the method of the present invention by any applicable route. subconjunctival, subretinal, suprachoroidal and retrobulbar. The choice of route by which a BSAT inhibitor is prescribed depends, in part, on whether retinopathy is being treated prophylactically or co-therapeutically. For therapeutic treatment, the choice of path depends on the cause of retinopathy. -

For example, since it is known that diabetes is the main cause of retinopathy, a BSAT inhibitor can be prescribed prophylactically as soon as the previous stage of diabetic retinopathy is established. For the preventive treatment of retinopathy that occurs as a result of diabetes, the systemic appointment of a BSAT inhibitor, for example, orally or by injection, is better. For the therapeutic treatment of non-proliferative diabetic retinopathy, the BSAT inhibitor can be prescribed systemically, for example, orally, or by injection, or intraocularly. Proliferative diabetic retinopathy can be treated therapeutically by intraocular, topical, subconjunctival, or periocular (e.g., subtenonal) administration of a BSAT inhibitor. For the prevention or "therapeutic treatment of retinopathy before, during or after surgical removal of scar tissue from the eye, which occurs as a result of neovascularization in the proliferative stage of diabetic retinopathy, the BSAT inhibitor is preferably prescribed intraocularly, locally, subconjunctivally or periocularly (for example, » subtenonal) ways.

A BSAT inhibitor is preferably prescribed as soon as possible after it has been determined that an animal such as a pet, in particular a human, is at risk for retinopathy (prophylactic treatment), or when retinopathy has already begun to develop (therapeutic treatment). In part, the treatment will depend on the specific BSAT inhibitor used, the amount of BSAT inhibitor prescribed, the method of administration, the cause and path of development of retinopathy. It is obvious to those skilled in the art that there are suitable routes of administration of the BSAT inhibitor applicable to the method of this 5p Invention. Several routes of administration can be used to prescribe a specific BSAT inhibitor, but

One of the ways always provides a faster and more effective reaction than the other. Therefore, the ways are described

They are intended to be purely demonstrative and do not limit all possible ways.

The dose prescribed to an animal, in particular to a human, according to the present invention should be sufficient to achieve the desired effect in the animal in an acceptable time. It is obvious to a person skilled in the art that dosage depends on various factors, including the strength of the particular BSAT inhibitor used, the age, species, course or phase of the disease, and body weight of the animal, as well as the expected or actual area of retinal damage. The amount of dosage (F, will also be determined by the route, frequency and duration of the appointment, as well as the presence, nature and significance of the undesirable side effects that may accompany the appointment of some BSAT inhibitors and the desired physiological effect. It is obvious to the expert that different conditions of the course or phase of the disease, particularly chronic 6p or phase conditions may require long-term treatment involving multiple appointments.

Applicable doses and dosing regimens can be established using conventional techniques known to those skilled in the art. In general, treatment is started with small doses, less than optimal. Then the doses are gradually increased until the optimal effect is achieved under the given circumstances. The method of this invention generally includes the administration of from about 1mg/kg/day to about 1OOmg/kg/day, preferably from about 15mg/kg/day to about BOmg/kg/day when administered systemically. A typical intraocular administration will include from about 0.1 mg to about 5 mg total dose, preferably from about 0.5 mg to about 1 mg total dose. The best concentration for local use is 100 mm.

Compositions for use in the method of this invention preferably include a pharmaceutically acceptable excipient and an amount of BSAT inhibitor sufficient to treat retinopathy prophylactically or therapeutically.

The carrier can be any of the commonly used ones, their use is limited only by physico-chemical considerations, such as solubility, reactivity in relation to the active component and route of administration. One skilled in the art will appreciate that in addition to the pharmaceutical compositions described below, the BSAT inhibitor can be used in polymer compositions, inclusion complexes such as cyclodextrin inclusion complexes, liposomes, microspheres, microcapsules and the like | see, for example, US Patent MM 4997652, 7/0 . 2185152 and 57189221

The BSAT inhibitor can be used in formulations as a salt of a compound of a pharmaceutically acceptable acid.

Examples of salts of compounds of pharmaceutically acceptable acids for use in pharmaceutical compositions include salts derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as tartaric, acetic, citric, malic, lactic, /5 fumaric, benzoic, glycolic, gluconic, amber and arylsulfonic, for example, p-toluenesulfonic.

Pharmaceutically acceptable excipients described herein, such as adjuvants, carriers or diluents, are well known in the art and are widely used in everyday life. Preferably, the carrier is chemically inert to the BSAT inhibitor and does not produce harmful side effects or toxicity under the conditions of use.

The choice of excipient is partially determined by the specific BSAT inhibitor, as well as by the specific route of administration of the composition. Accordingly, there is a wide variety of applicable formulations of the pharmaceutical compositions of this invention. The following recipes are purely demonstrative and do not limit the possible options.

Formulations for injections, among others, are preferred for the method of this invention. The requirements for pharmaceutically effective carriers for injectable compositions are well known to those skilled in the art | see Rpaptaseciysv apa Rpagtasu sch

Rgasiise, U.V. Iirripsoi So., RPyYadeIrnia, Ra., VapKeg apa Spaitegv, edv., radez 238-250 (1982), and AVBNR

Naparook op Ipiesiabie Ogydv, ToivzeI, 4 ey., radez 622-630 (1986)). It is preferable that such compositions, which i9) are injected, are prescribed intramuscularly, intravenously or intraperitoneally.

Local prescriptions are well known to specialists. Such formulations are applicable in the context of this invention for application to the skin. The use of bandages, corneal shields (see, e.g., U.S. Patent He Me5185152) and ophthalmic solutions (see e.g. U.S. Patent Me57101821) and ointments, e.g., eye drops, are also well known. -

Formulations suitable for oral administration may include (a) liquid solutions such as an effective amount of the compound dissolved in a diluent such as water, saline or orange juice; (b) capsules, sachets, tablets, cakes and lozenges, which contain a certain amount of the active component in solid form or in granules; (c) powders; (d) suspensions in a suitable liquid and (e) emulsions. Liquid formulations - may include diluents such as water and alcohols such as ethanol, benzyl alcohol and polyethylene alcohols, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Capsule forms may be conventional hard or soft shells filled with, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include, alone or in combination, lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, stearate magnesium, calcium stearate, zinc stearate, stearic acid and other fillers, dyes, thinners, buffers, looseners, humectants, preservatives, flavoring agents and pharmacologically compatible fillers. gum arabic or tragacanth; lozenges include an active component in an inert base, such as gelatin and glycerin, or sucrose and gum arabic; emulsions, gels and similar forms contain, in addition to the active component, fillers known to specialists. of transfer through the mucous epithelium | its stability in the intrahepatic circulation and effective parenterally, but less effective orally, or whose plasma half-life is very short, may be chemically

Kz are modified in the form of prodrugs.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions for injection, which may contain antioxidants, buffers, bacteriostatics and substances that maintain an isotonic state with respect to the blood of the recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickeners, stabilizers and preservatives. The inhibitor can be prescribed together with

F, a physiologically acceptable diluent in a pharmaceutical excipient, such as a sterile liquid or a mixture of liquids, including water, saline, aqueous dextrose and solutions of related sugars, an alcohol such as ethanol, isopropanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol dimethyl sulfoxide, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, esters such as poly(ethylene glycol) 400, oil, fatty acid, fatty acid ester or glyceride, or acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or detergent, a suspending agent such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or an emulsifying agent and other pharmaceutical adjuvants. Oils that can be used in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed,

corn, olive, vaseline and mineral oil.

Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

Suitable soaps for use in parenteral formulations include alkali metal fatty acid salts, ammonia and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides and alkylpyridine halides, (b) anionic detergents such as, e.g. , alkyl, aryl, and olefin sulfonates, sulfates of aalkyl, olefin, ether, and monoglycerides, and 7/0 bulfosuccinates, (c) nonionic detergents, such as, for example, fatty acid amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents, such as, for example, alkyl-p-aminopropionates and quaternary ammonium 2-alkyl-imidazoline salts and (e) their mixtures.

Parenteral formulations will typically contain from about 0.5 to about 25 weight percent of the active ingredient in solution. Preservatives and buffers may be used. In order to reduce or prevent irritation at the injection site, such compositions may contain one or more nonionic surfactants with a hydrophilic-lipophilic balance (HLB) of about 12 to about 17.

The amount of surfactant in such formulations should vary from about 5 to about 15 kg.95. Suitable surfactants include fatty acid esters of polyethylene sorbitan, such as sorbitan monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of 20 propylene oxide with propylene glycol. Parenteral formulations may be presented in single-dose or multi-dose containers, such as ampoules and vials, and may be stored in lyophilized form, requiring only the addition of a sterile liquid excipient, such as water, for injection immediately prior to use. Solutions and suspensions for immediate use can be prepared from sterile powders, granules and tablets of the previously described types. high school

Such compositions can be formulated as intraocular formulations, as formulations or devices for prolonged administration (see, for example, US Pat. No. 5,378,475). For example, gelatin, chondroitin sulfate, a polyphosphoester such as bis-2-hydroxyethyl terephthalate (BGET) or polylactic acid (in varying proportions) can be used to create long-acting formulations. Implants can be used |see, for example, US patents Mo5443505, 4953224 and 49976521, devices |see, for example, US patents Mo5554187, 4863457, c zo 9098443 | 5725493), such as implantable devices, such as a mechanical reservoir, intraocular devices, or extraocular devices with an intraocular channel (eg, 1000 µm to mm in diameter), or - devices comprising polymeric compositions such as those described above. yu

The method of this invention may also include co-administration of other pharmaceutically active components. "Concomitant appointment" means appointment before, at the same time, for example, in combination with an inhibitor o

BSAT, in the same formulation or in a separate formulation, or after the appointment of a BSAT inhibitor, as described above. uh-

For example, corticosteroids such as prednisone, methylprednisolone, dexamethasone or trimasinalone acetinide or non-corticosteroid anti-inflammatory compounds such as ibuprofen or flubiproben may be co-administered. Similarly, vitamins and minerals, naoriclade, zinc, antioxidants such as carotenoids (such as xanthophyll carotenoids such as zeaxanthin or lutein), and trace elements may be co-prescribed. General synthesis schemes for the preparation of Formula I-IM compounds. . EXAMPLE 1: trans-"1Kk,3K)(1-aminomethyl-3-methyl-cyclohexyl)-acetic acid hydrochloride ke i r rech re: page -I Ii. and I and SE M, and Y. g sooEh ih 5 kv r shNoyasI yu o tr, nor, a 60 () EBSSNOSM, MN.AS, AsoNn, toluene, 12020 (i) a. MasM, EUUN (9595), NO, 1152S, 6. NSI (gas) (ii) EUON, NS! (gas), toluene (m) НС, НО (М) Но, ЕУН/МН", Mi Raini, 30-502С 65 (mi) NSI, NDO, 14090

Stage i: 2-cyano-(K)-3-methyl-cyclohexylidene)-acetic acid ethyl ether

A mixture of 3-(K)-methylcyclohexanone (125 mmol), ethyl cyanoacetate (124 mmol), ammonium acetate (12.5 mmol), and glacial acetic acid (24 mmol) was refluxed with a Dean Stark trap for 24 hours. The mixture was cooled and washed with NO. The NaOH wash was extracted with toluene. Toluene extracts were combined with the obtained organic phase, dried over MAOSO, and the solvent was evaporated. The crude oil preparation was purified by Kugelror distillation to obtain oil (boiling point 150-1602C). Output 8690. "YAN NMR (SOS) 400MHz 5: 1.01-1.05 (ZN, t), 1.17-1.32 (IN, t), 1.35 (ZN, 6, 9-7GuC), 1.42-2.30 (6Н, t), 2.98 (1H, a, 9U-13Hz), 3.74 (1H, a, U-13Gu), 4.27 (2H, a, 9-7Hz)

Mass spectrometry (SI) m/z: 208 (MN")

Microanalysis: С42Н47МО»

Calculation: C 69.54 H 8.27 M 6.76;

The result of the analysis: C 69.44 H 8.22 M 6.76

Her stage: trans-(1K,3K)-1-cyanomethyl-3-methyl-cyclohexanecarbonitrile

15. 2-cyano(K)-3-methyl-cyclohexylidene)-acetic acid ethyl ether (40 mmol) was added to a solution of Masm (40 mmol) in 6 ml of NO and 160 ml of ethanol (9595). After 22 hours of refluxing, the cooled solution was filtered, the filtrate was acidified with gaseous NSII and filtered again. The solvent was removed and the crude oil was purified by column chromatography to give a pale yellow crystalline solid. Exit 8895.

TN nMR (SOSIi) 400 MHz 5: 0.90 (1H, t), 0.98 (ZH, a, 9-6Hz), 1.11 (IN, 5 9-12Hz), 1.38 (1H, a, 4-4.9Gu), 1.60- 1.90 (4H, t), 2.07 (2H, t), 2.68 (2H, c)

Mass spectrometry (SI) m/z: 163 (MN")

Microanalysis: SONG Mo

Calculation: C 74.04 N 8.70 M 17.27;

The result of the analysis: C 74.05 H 8.71 M 17.25 s 29 Stages: trans-2-(1Kk,3Kk)-1-cyano-3-methyl-cyclohexyl)-acetimidic acid ethyl ether He)

30 ml of dry toluene was added to a solution of trans-(1k,3K)-1-cyanomethyl-3-methyl-cyclohexanecarbonitrile (6b.2mmol) in 30ml of ethanol (absolute). The solution was cooled in ice, while saturating it with gaseous NS. The closed solution was then left at room temperature for 24 hours. The solvent was removed and the solid residue was triturated with diethyl ether to give a precipitate which was dried to give a white crystalline solid. Exit 50905. -

Trpl 118-120 u "H NMR (DMSO) 400MHz 6: 0.8-0.89 (1H, t), 0.91 (ZH, a, 9-6.3Hz), 1.06-1.12 (1H, t), 1.24-1.35 (1H, t), 1.37 (ZN, 6, 9-7Gu), 1.41-1.95 (6H, t), 3.02 (2H, c), 4.49 (2H, a, 9-7Hz) Shcheo,

Mass spectrometry (SI) m/z: 195 (MN") ch

Microanalysis: С42НооМ20.1.08М NS

Calculation: C 58.19 H 8.58 M11.31;

The result of the analysis: C 58.25 H 8.59 M 11.59

Stage im: trans-"(1K,3K)-1-cyano-3-methyl-cyclohexyl)acetic acid ethyl ether"

Trans-2-(1kK,3K)-1-cyano-3-methyl-cyclohexyl)-acetimidic acid ethyl ether (1.1 mmol) was dissolved in pt) with ice-cold HO (40 ml) and the pH of 1 M NOI was adjusted to pH 1.5. The solution was stirred at room temperature for 20 hours. and Ethyl acetate (30ml) was added and the organic layer was washed with NaOH, dried and the solvent was removed to give a clear oil. Exit 8290.

TN NMR (SOSIi) 400MHz 5: 0.78-0.90 (IN, t), 0.93 (ЗН, а, 9-6Hz), 0.97-1.00 (1Н, т), 1.23-1.25 (1Н, t), 1.29 (ЗН, 6. 9-7.2Hz), 1.59-1.80 (4H, t), 2.05-2.08 (2H, Vi U, 2.54 (2H, c), 4.20 (2H, a, 9-7.2Hz) - Mass spectrometry (SI ) m/z: 210 (MN") s Microanalysis: С42Н4и19МО»

Calculation: C 68.87 H 9.15 M 6.69; o Analysis result: C 68.87 H 9.11 M 6.90 - 20 Stage M: Trans-(B5K, 7K)-7-methyl-2-aza-spiroI(4.5)|decan-3-one

Trans-(1kK,3K)-1-cyano-3-methyl-cyclohexyl)acetic acid ethyl ether (8.9 mmol) was dissolved in MNUZ/EUN (795, 40 ml) together with pre-washed Raney nickel (HO, then EN) in a 250 ml Parr flask.

The solution was hydrogenated at 302C, 46 bar, for 24 hours. The cooled solution was filtered through a celite pad washed with ethyl acetate. The solvent was removed from the filtrate to give a white solid. Exit OO ZO9r5.

Ge) Tpl 92-982С kyu TN nNMR (DMSO) 400MHz 5: 0.75-0.82 (IN, t), 0.84 (ZN, a, U-6.4Hz), 0.88-0.94 (1Н, t), 1.14-1.19 (1Н , t), 1.20-1.50 (2H, t), 1.50-1.63 (4H, t), 1.91 (2H, c), 3.03 (2H, 5), 7.42 (1H 8) in from: 168 (MN")

Microanalysis: S.0Н47МО

Calculation: C 71.81 N 10.25 M 8.37;

The result of the analysis: C 71.80 H 10.29 M 8.31

Step 1: trans-(1k,3k)-1-aminomethyl-3-methyl-cyclohexyl)-acetic acid hydrochloride and Trans-(lk,7kk)-7-methyl-2-aza-spiro(4.5)decane-33- he (2.17 mmol) was dissolved in a solution of TOM NSI (5 ml) and HO (bBml), and the mixture was refluxed at approximately 1402C for 5 hours. The cooled solution was diluted with 10 ml of HO and 10 ml of OSM, and the aqueous layer was then washed twice with 15 ml of OSM. The aqueous layer was concentrated to dryness to give a white solid. Exit 76905.

Postal code 148-15522. (o; |p--2.5 (T-202C, c-1, Meon). One isomer (KK). "YAN NMR (SOS) 400 MHz 5: 0.69-0.79 (1Н, t), 0.82 (ЗН, а, 9-6Hz), 0.87-0.90 (IN, t), 1.12-1.20 (1Н, yes, 4-4.5, 13.3Hz), 1.34-1.50 (ЗН, t), 1.60-1.63 (ЗН, t), 2.30 ( 2H, c), 3.01 (2H, c), 7.93 (ZH, Vg c)

Mass spectrometry (SI) m/z: 186 (MN")

Microanalysis: С.оН4л19МО». 1.1 NS

Calculation: C 53.29 H 8.99 Mb6.21;

The result of the analysis: C 53.23 H 8.99 M 6.45

EXAMPLE 2: (1-Aminomethyl-2-methyl-cyclohexyl)-acetic acid hydrochloride was produced in

Cotton wool: AY "ROZA and Mk her, Her and EBSSNOSM, MN.AS AsoNn, toluene, 120260 sch zo her. and. MasM, EUN (9595), H2O, 1152С, 6. NSII (gas) her. EN, NS! (gas), toluene in them. We don't know, but I do

M. Noh, EUN/MChN", Mi Rainey, 30-50

E. NS, NhO, 1402C that)

Stage i: 2-cyano-(2-methyl-cyclohexylidene)-acetic acid ethyl ether h-

The reaction of (17-)2-methylcyclohexanone (80 mmol), ethyl cyanoacetate (80 mmol), ammonium acetate (8 mmol) and glacial acetic acid (1 mmol) was carried out as a step of the general method (Example 1) to obtain a clear oil. Exit 7690.

TN NMR (SOSI) 400MHz 5: 1.23 (ZN, aa, 9-7, 10Hz), 1.35 (ZN, 5, 9U-7Hz), 1.55-1.82 (BN, t), 1.93-2.05 « 400 (NN, t ), 2.17 (1H, a 9-5, 14Hz), 2.47 (1H, ab 9-5, 9Hz), 2.92-2.97 (1H, Vg, a, U-15Hz), 3.30-3.35 (1H, t), - s 3.81-3.86 (1H, Vga, U-15Hz), 4.06-4.14 (1H, t), 4.23-4.30 (ZH ad,o-1.6Hz) m Mass spectrometry (SI) m/z: 208 ( МН") » Microanalysis: С42Н.47МО»

Calculation: C 69.54 H 8.27 M 6.76;

The result of the analysis: C 69.26 H 8.26 M 6.66 - Step her: i-cyanomethyl-2-methyl-cyclohexanecarbonitrile sl Reaction of 2-Cyano-(2-methyl-cyclohexylidene)-acetic acid ethyl ether (3/mmol) and Masm (37mmol) was carried out as in Step 1 of Example 1. The crude preparation of the solid substance was purified by column chromatography with (311 heptane-ethyl acetate) to obtain a clear oil. Output 7690. -I 20 "YAN yNMR (SOSIZ) 400MHz 5: 1.06 (ZN, a, 9U-6.8Hz), 1.11 (ZN, a, U-6.8Hz), 1.20-2.20 (18Н, t), 2.77 ( 2H, ad, U-16.8Hz), 2.63 (2H, aa, 2-16.8Hz) mass spectrometry (SI) m/z: 163 (MN")

Microanalysis: С.40Н44М20.1 НО

Calculation: C 73.49 H 8.69 M 16.86; 99 The result of the analysis: C 73.24 H 8.73 M 17.08

HF) Step ii: 2-(1-cyano-2-methyl-cyclohexyl)-acetimidic acid ethyl ether t The reaction of 1-Cyanomethyl-2-methyl-cyclohexanecarbonitrile (7.3 mmol) was carried out as in Step iii of Example 1 with the production of a white solid . Exit 70905.

Trpl 107-11426 bo TN nMR (DMSO) 400 MHz 5: 1.00-1.06 (ZN, 2хи, 9-6.4ГЦ), 1.10-1.38 (2Н, т), 1.38 (ЗН, 6 9-6.8ГХ), 1.40-2.10 (7Н, t), 2.86, 2.92, 3.10, 3.28 (2Н, 4ха, 9-14, 14.4, 14.8 14Гц, respectively), 4.48 (2Н, а, У-6.8Гц)

Mass spectrometry (SI) m/z: 209 (MN")

Microanalysis: С42НооМ20.1.06М NS 65 Calculation: С 58.37 Н 8.60 М 11.34;

The result of the analysis: C 58.15 H 8.63 M 11.60

Step 1: (1-cyano-2-methyl-cyclohexyl)-acetic acid ethyl ether

The reaction of 2-(1-cyano-2-methyl-cyclohexyl)-acetimidic acid ethyl ether (4.1 mmol) was carried out as in

Stage (im) of Example 1 with the production of clear oil. Output 82905. "YAN yNMR (SOSIZ) 400MHz 5: 1.03, 1.09 (ZN, 2ha, 9-7Hz), 1.27-1.30 (ZN, t), 1.32-2.00 (VN, t), 2.10-2.20 (IN, t ), 2.44, 2.82 (ZN, 2xd, 9U-14.8Hz), 2.54 (1H, t), 4.16-4.22 (2H, t)

Mass spectrometry (SI) m/z: 210 (MN")

Microanalysis: О42Н49МО»2

Calculation: C 68.87 H 9.15 M 6.69;

The result of the analysis: C 68.84 H 9.13 M 6.75

Step M: 6-Methyl-2-aza-spiro|4.5)decan-3-one

The reaction of (1-cyano-2-methyl-cyclohexyl)-acetic acid ethyl ether (8.4 mmol) was carried out as in Step (M)

Example 1 for 24 hours at 102C 5 Orv. The crude oil preparation was purified by column chromatography (ethyl acetate) to give a white solid. Exit 3490.

Postal code 85-9026;

TN NMR (SOSI) 400MHz 5: 0.88-0.91 (ZN, aa, 4-4, 6.8Hz), 1.41-1.78 (9Н, т), 2.00-2.30 (2Н, т), 3.06-3.23 (2Н, т) , 7.27 (1 N, Vg in)

Mass spectrometry (SI) m/z: 168 (MN")

Microanalysis: C10iH-7MO

Calculation: C 71.81 H 10.24 M 8.37;

The result of the analysis: C 71.83 H 10.19 M 8.27

Step 1: (1-aminomethyl-2-methyl-cyclohexyl)-acetic acid hydrochloride

The reaction of 6b-Methyl-2-aza-spiro(4.5|decan-3-one (2.5 mmol) was carried out as in Step (mi) of Example 1 with the production of a white solid. Yield 4295. cm

Tll 108-1109S. o (o. 10-20 (1-20.59C, C-1, Meon). Two diastereomers 3:1. "H NAM, (DMSO-0O20) 400MHz 5: 0.79, 0.85 (ZN, 2ha, U-6.8Hz ), 1.21-1.65 (9Н, т), 2.22, 2.43 (1Н, 2ха,

U-15Hz), 2.46, 2.49 (1H, 2ha, 9U-15Hz), 2.83-2.92 (1H, 2ha, 9-13.6Hz), 3.05, 3.15 (1H, 2ha, 9-15Hz), 246 249. YDSh SI 30 AN, 2xda, 9-15Gu), 2.83-2.92 (1H, 2kha, 9U-13.6Gu), 3.05, 3.15 (1H, 2kha, 2-13.6Hz).

Mass spectrometry (SI) m/z: 186 (MN") he

Microanalysis: С1оНиоМО».1.3 NSI iv)

Calculation: C 51.64 N 8.79 M 6.02; yu

The result of the analysis: С 51.66 Н 8.91 М 6.16 35 EXAMPLE C (1-aminomethyl-3,3-dimethyl-cyclohexyl)-acetic acid hydrochloride - smears it and « 45 flesh: 8. ебАН: Mykh - gy Yak--yani ten Czech Republic, 1 Vocational Technical University Czech Republic. and I, yes, and I. and. Si, Mei her, MNASI, MN", (9295) her. MSSNOSOBY, MNAaOAs, AsonH, toluene, (8390) and, Masm, EN, NS, (5795)

GF) to them. NSI, EUN, toluene, (9390) 7 MN", Mi Rainey, EUN, MN", (84965) mi. NCI, H2O, (6496) in Step i: 3,3-dimethyl-cyclohexanone:

Synthesized by the method (described in Reiieg, 5. MU., Modu, M. M., U. Oga. Spet., 1976, 41, 1069).

A solution of lithium dimethylcuprate was prepared by adding methyllithium (1.4M in ether, 77.25ml, 2.45mol) to copper iodide (I) (8.8g, 0.046mol) in an argon atmosphere. The solution was cooled to 09°C and added dropwise

3-methyl-cyclohexen-1-one (5 ml, 0.044 mol) with stirring, after which a precipitate of intense yellow color was formed. The suspension was stirred at room temperature for one hour, then poured into a solution of aqueous ammonia (100 ml) and ammonium acetate (5 g). The layers were separated and the aqueous layer was washed with diethyl ether (3 x 5 mL).

The combined organic phase was washed with saturated saline solution (3X100 ml), dried (M950,) and the solvent was removed under vacuum to obtain a dark yellow liquid. "H NMR (400 MHz, SOSI") 0.98 (6H 5), 1.59 (2H, t), 1.88 (2H, t), 2.14 (2H, t), 2.26 (2H, t).

IR spectroscopy (film) at tach SM"! 2956, 1711 (C-0), 1457, 1368, 1292, 1226, 1076.

Stages: 2-cyano-5,5-dimethyl-3-propyl-hex-2-enoic acid ethyl ether

To a solution of 3,33-dimethylcyclohexanone (4 g, 0.032 mol) in toluene (25 mL) was added ethyl cyanoacetate (3.37 mL, 0.032 mol, 0.2 eq.), ammonium acetate (0.24 g, 0.003 mol, 0.1 eq.), and acetic acid ( 0.Zbml, 0.006Mol, 0O.2eq.). The yellow solution was heated to boiling under a reflux condenser with a Dean-Stark trap, and heating was continued until water ceased to condense in the trap. After cooling, the now yellow-hot solution was washed with water (Zh 25 ml) and the organic layer was dried (M950,). Filtration and removal of the solvent under vacuum gave the crude product as a dark yellow-hot liquid. After purification by Kugelror distillation, a mixture of cis and trans products was obtained in the form of a pale yellow liquid, boiling point 160-1702С, 4mbar (5.83g, 8390).

TN NMR (400 MHz, SOCI3) 0.96 (6H, 5, 2x Me), 0.99 (6H, 5, 2x Me), 1.34 (6H, t, 2x Me ethers), 1.49 (4H, t), 1.75 (2H, quine ., 96.4), 1.82 (2H, chin., 96.4), 2.46 (2H, 5), 2.60 (2H, 5 -6.4HC) 2.80 (2H, c), 2.93 (2H, 1, 9U-6.4HC), 4.27 (4H, t).

Mass spectrometry (SI) with/e: 222 (M'-1)

IR spectroscopy (film) in a bird" 2958, 2870, 2224 (SM), 1731 (S-O), 1606 (S-S), 1277, 1223.

Microanalysis: О43Н41902М

Calculation: C 70.56 N 8.65 M 6.32;

The result of the analysis: C 70.35 H 8.79 M 6.25

Her stage: 1-cyanomethyl-3,3-dimethyl-cyclohexanecarbonitrile

Sodium cyanide (0.28g, 0O .006 bMole, Current). The yellowish solution was boiled under reflux for 8 hours, then cooled, during which a muddy white precipitate was formed.

The suspension was filtered under vacuum and the filtrate was acidified with gaseous HCl to approximately pH2. Then the mixture was filtered a second time and the solvent was removed under vacuum to give the crude product in the form of a pale green thick solid.

Flash column chromatography of the crude product on silica gel with an elution of 0-5095 E(Ac in heptane gives their binitril in the form of a colorless solid (0.57g, 57905).

TN nMR (400 MHz, SOCI3) 0.99 (ZN, 8, Me), 1.13 (IN, (4, 713.2, 4.2), 1.21 (ZN, 5, Me), 1.32 (2H, t), 1.54 (1H, t) . , 46.26, 115.06, 122.19. M

Mass spectrometry (SI) with/e: 177 (M"-1)

IR spectroscopy (film) in a bird" 2988, 2937, 2237 (2XCM), 1749, 1456, 1423, 1369, 1202, 1180, 1031,972.

Microanalysis: P.44 H4vMo "

Calculation: C 74.96 H 9.15 M 15.89;

The result of the analysis: C 75.08 H 9.32 M 15.80 - s Step im: (1-cyano-3,3-dimethyl-cyclohexyl)-acetic acid ethyl ether: and 1-cyanomethyl-3,3-dimethyl-cyclohexanecarbonitrile (0.50g, 2.84 mmol) was dissolved in absolute ethanol (20 ml) at room temperature, then cooled to 02C. Toluene (20 ml) was added to the solution, after which the reaction mixture was acidified by passing it through gaseous NCI at a low speed for 45 min. Then the flask was stoppered and left at room temperature for 24 hours. - The obtained yellow solution was distributed between the phases of ethyl acetate and water, the layers were separated. The aqueous layer was extracted with ethyl acetate (3x 30ml), the combined organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate (3x 5Oml), brine (3x 5Oml), dried (Ma5ZO)) and the solvent was removed under 1 reduced pressure to obtain a pale yellow liquid (0.59g, 93905). - and 250 "IN NMR (400 MHz, SOS") 0.94 (ZN, in, Me), 1.16 (ZN, t), 1.21 (ZN, in, Me), 1.29 (ZN, i, 27.2, СНоСН»У), 1.50 (1H, t), 1.65 (1H, ab 14.4, 7.6), 1.84 (1H, di, 913.3, 3.2), 1.96 (IN, ak 913.7, 2.2), 2.16 (1H, t), 2.48 .

ZS NMR (400 MHz, SOSIZ) 14.21, 16.95, 25.42, 31.03, 34.04, 34.14, 36.08, 38.44, 46.14, 46.80, 61.02, 123.67, 169.00. 25 Mass spectrometry (SI) with/e: 224 (M"-1) (F, IR spectroscopy (film) in the bird"! 2998, 2937, 2868, 2234 (SM), 1738 (С-О), 1457 , 1372, 1217,1181, 11541026. ka Microanalysis: С43Н243МО»

Calculation: C 69.92 H 9.48 M 6.27; in The result of the analysis: C 69.63 H 9.45 M 6.15

Step M: 7,7-dimethyl-2-azo-spiro-(4,5|decan-Z-one: (1-cyano-3,3-dimethyl-cyclohexyl)-acetic acid ethyl ether (0.5g, 2.23mmol ) was hydrogenated in ethanolic ammonia (bOml) with Raney nickel as a catalyst (0.25 g) at 502C and 5 Org for 48 hours.

Then the catalyst was removed by filtration through celite, and the solvent was removed under vacuum to give b5 as a yellowish crystalline substance.

Flash column chromatography eluting with 0-10095 ethyl acetate in heptane afforded the pure lactam as a colorless solid (34mg, 8490).

TN NMR (400MHz, SOSIZ) 0.89 (ZN, z, Me), 0.92 (ZN, 5, Me), 1.25 (2Н, т), 1.36 (2Н, т), 1.51 (ЗН, т), 1.68 (1Н, 5), 2.18(1H, a, 916.4, CHNOMH), 2.24 (1H, α, 216.8, CHNOMH), 3.15 (2H, 5, CHNOSO). 13C NMR (400 MHz, SOSI") 19.16, 29.88, 30.36, 31.28, 36.57, 39.05, 39.61, 44.58, 49.54, 54.79, 177.72.

Mass spectrometry (SI) with/e: 182 (M'-1)

IR spectroscopy (film) at tachsm' 3203, 3100 (MN), 2914, 2860, 1698 (С-0), 1486, 1374, 1317, 1289, 1257, 1076.

Microanalysis: P.4 No MO

Calculation: C 72.88 N 10.56 M 7.73;

The result of the analysis: C 72.38 H 10.47 M 7.56

Step 1: (1-aminomethyl-3,3-dimethyl-cyclohexyl)-acetic acid hydrochloride: 7,7-dimethyl-2-azo-spiro-14,5-decan-3-one (0.3 g, 1.6 mmol) was dissolved in a mixture of CARRIER (conc., bml) and water (ml) and the obtained colorless solution was refluxed for 20 hours, the solution was cooled and 79 was distributed between water and dichloromethane, after which the layers were separated. The aqueous layer was washed with dichloromethane (Zh 20ml) and water and NSI were removed in a rotary evaporator to give the crude product as an off-white solid. Trituration with ethyl acetate and filtration of the product gave (1-aminomethyl-3,3-dimethyl-cyclohexyl)-acetic acid hydrochloride as a colorless solid (14Omg, 4290, 6495 based on the starting material used). "IN NMR (400 MHz, DMSO) 0.90 (ZN, c, Me), 0.92 (ZN, c, Me), 1.15-1.49 (8H, t), 2.45 (2H, 5, СНоСОЗН), 2.90 (2Н, bg. a, 913.5, SNOMN"), 7.96 (ЗН, Bg.5, МН"), 12.36 (1Н, Bg.5, ОН).

IR spectroscopy (film) in tachs"! 2930, 1728(С-0), 1272, 1123.

Microanalysis: С.44Но2МО»СИ сч re Calculation: С 56.04 Н 9.41 М 5.94;

The result of the analysis: C 55.79 H 9.61 M 6.23 (o)

EXAMPLE 4: (17-)-(trans)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride

JOZEE "I OZ sch zo | . y : | -y schi

Kay t. I still

P HER Sho chai yu

M pk: is bvasozh r. shche she chi. "U and ! g! yes yes yes

Oh winiyau shchi-chavu hands) "

I shi s v 7 h» shi son Y i tnahu 7 Shk y y i- U "vh 7 shi -.70 " d 7 y SYA

Co.)

Reagents: (i) triethylphosphonoacetate, Ma; (i) Memo», You M"Eg; (iiii) N", Mi; (im) NSI

Stage i: synthesis of (47-UHutrans)-(3,4-dimethyl-cyclopentylidene)-acetic acid ethyl ether (465)

Ma (6095 dispersion in oil, 737 mg, 18.42 mmol) was suspended in dry tetrahydrofuran (5 Oml) and cooled to 02С. Then triethylphosphonoacetate (3.8 ml, 19.30 mmol) was added and the mixture was stirred at 02 for 15 minutes. Then, ketone (/-)-(4a) (1.965g, 17.54mmol) in THF (10ml) was added and the mixture was allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 ml) and water (150 ml).

The organic phase was separated, washed with saline, dried (Ma5O)) and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel, ethylacetate-teptane 1:9) to obtain 3.01 g (9496) (45) in the form of a colorless oil.

TN NMR 400MHz, (SOSIv): 5 1.01 (ZM, a, U-6GHz), 1.03 (ZN, a, 9-6Hz), 1.26 (ZN, 5, 9-7Hz), 1.49 (2H, t), 2.07 (1H, t), 2.24 (1H, t), 2.61(1H, t), 4.13 (2H, ad, 9-7 Hz), 5.72 (1H, z)

Mass spectrometry (Sik) m/e: 183 (M'-1) for Stages: synthesis of (47-Xtrans)-(3,4-dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ether (4c)

(4"XTrans)-(3,4-dimethyl-cyclopentylidene)-acetic acid ethyl ether (45) (2.95 g, 16.2 mmol) was dissolved in tetrahydrofuran (1 mL) and stirred at 702 with nitromethane (1.9 mL, 35.2 mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 22ml, 22.0mMol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50ml) and washed with 2M NOSI (30ml) and then with saline (50ml).

The organic phase was collected, dried (Mo950,) and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel, ethyl acetate:heptane 1:9) to obtain 1.152 g (29965) of a clear oil. "IN NMR 400MHz, (SOSIv): 5 0.98 (EM, a, U-6Hz), 1.10-1.39 (5Н, т), 1.47 (2Н, т), 1.87 (IN, т), 2.03 (1Н, т) .

Mass spectrometry (EbB'k) m/e: 244 (M'-1)

IR spectroscopy (film) in cm"!: 1186, 1376, 1549, 1732, 2956.

Stage 1: synthesis of (17-)-(trans)-7,8-dimethyl-spiro(4,nonan-2-one (484) (17-Xtrans)-(3,4-dimethyl-1-nitromethyl-cyclopentyl) -acetic acid ethyl ether (4c) (1.14g, 4.7mmol) was dissolved in methanol (50ml) and shaken over the Raney nickel catalyst in a hydrogen atmosphere (4Og) at 3026. 75 After 5 hours, the catalyst was removed by filtration through Celite. The solvent was removed under vacuum with obtaining 746bmg (9595) of a pale yellow oil, which then solidified. "IN NMR 400MHz, (SOSI"): 5 0.98 (EM, a, U-6GHz), 1.32 (2H, t), 1.46 (2H, t) , 1.97 (2H, t), 2.27 (2H, АВа,

U-16,27HuCs), 3.23 (2H, 8), 5.62 (1H, bgv).

Mass spectrometry (Eb'k) m/e: 168 (M'-1)

IR spectroscopy (film) in cm": 1451, 1681, 1715, 2948, 3196.

Step 1: synthesis of (7-)-(trans)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride (4) (4/-)-("Trans)-7,8-dimethyl- spiro|(4,nonan-2-one (44) (734 mg, 4.40 mmol) was refluxed in a mixture of 1,4-dioxane (bml) and EM NOSI (15 ml). After 4 hours, the mixture was cooled to room temperature temperature, diluted with water (20ml) and washed with dichloromethane (3x 30ml). The aqueous phase was collected and the solvent was removed under vacuum. The residue was triturated with ethyl acetate and after collection and drying, 675mg (o) (69905) of a white solid was obtained.

TN NMR 400MHz, (de-DMSO): 5 0.91 (6H, 4, 9U-6Hz), 1.18 (2H, t), 1.42 (2H, t), 1.72 (1H, t), 1.87 (1H, t), 2.42 (2H, AVa, 9U-16.24Hz), 2.90 (2H, AVa, uU-12.34Hz) 8.00 (ZN, Bgv), 12.ZA(1H, rBgv). Ha

Mass spectrometry (ESB) m/e: 186 (M.--1 for the free base form).

EXAMPLE 5 (cis/trans)-(3K)-(1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride (5) - : ейі Жі Жі Е and 1. ч- г піт те З і? - shko that zada voki «sl r: more Z and E k and K ; -0.720 Bei schy I r. and from Ku no uva

Reagents: (ii) triethylphosphonoacetate, Ma; (i) Memo", VYAM NE; (iii) No", Mi; (im) NSI o Step i: synthesis of (K)-(3-methyl-cyclopentylidene)-acetic acid ethyl ether (55)

Ma (6095 dispersion in oil, 1.87 g, 46.5 mmol) was suspended in dry tetrahydrofuran (4 Oml) and 60 was cooled to 02С. Then triethylphosphonoacetate (9.69 ml, 48.8 mmol) was added and the mixture was stirred at 02 for 15 minutes. Then (K)-33-methyl-cyclopentanone (5a) (mL, 46.5 mmol) in THF (10 mL) was added and the mixture was allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (2000ml) and water (1500ml). The organic phase was separated, washed with saline solution, dried (Ma95O)) and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel, ethyl acetate-teptane 1:9) to give 5.45 g (70905) (2) as a colorless oil.

"YAN NMR 400MHz, (SOSIia): 5 1.04 (ZM, t), 1.27 (NN, 5, 9-7Hz), 1.80-2.74 (7Н, t), 2.90-3.15 (1Н, t), 4.13 (2Н, a, 9-7Hz), 5.76 (1H, c).

Mass spectrometry (Sik) m/e: 169 (M'-1)

IR spectroscopy (film) in cm": 1205, 1371, 1653, 1716, 2955.

Its stage: synthesis of (cis/trans)-(3K)-(3-methyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ether (5c) (K)-(3-Methyl-cyclopentylidene)-acetic acid ethyl ether ( 5) (3.0 g, 17.4 mmol) was dissolved in tetrahydrofuran (1 mL) and mixed at 709C with nitromethane (1.92 mL, 35.bmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 25 mL, 25.00 mmol). After 18 hours, the mixture was cooled to room temperature at 70°C, diluted with ethyl acetate (50ml) and washed with 2M NaOH (30ml) and then with saline (50ml).

The organic phase was collected, dried (Mo950,) and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel, ethyl acetate:heptane 1:9) to obtain 2.00 g (4995) of a clear oil. "NN NMR 400 MHz, (SOSIv): 5 1.02 (ZM, a, uU-bgc), 1.08-1.37 (BN, t), 1.59-2.17 (5Н, t), 2.64 (2Н, т), 4.15 (2Н, a, 9-7Hz), 4.64 (2H, t). 12 Mass spectrometry (EBu) m/e: 230 (M'-1)

IR spectroscopy (film) in cm"!: 1183, 1377, 1548, 1732, 2956.

Its stage: synthesis of (cis/trans)-(7kK)-7-methyl-spiro(4,A|nonan-2-one (54) (cis/trans)-(3K)-(3Z-methyl-1-nitromethyl -cyclopentyl)-acetic acid ethyl ether (5c) (1.98g, 8.6bmol) was dissolved in methanol (50ml) and shaken over a Raney nickel catalyst in a hydrogen atmosphere (4Oz) at 3026.

After 18 hours, the catalyst was removed by filtration through Celite. The solvent was removed under vacuum and the residue was purified by flash chromatography (silica gel, ethyl acetate:heptane 1:11) to give 1.05 g (7990) of a white solid. "H NMR 400 MHz, (SOSIa): 5 1.03 (ZM, t), 1.22 (2M, t), 1.60-2.15 (BN, t), 2.22 (2H, t), 3.20 and 3.27 (2H, total, 2 x 8, TsiIS I trans), 6.18 (1H, rg 5).

Mass spectrometry (EBu) m/e: 154 (M'-1) and)

IR spectroscopy (film) in cm"1:1695, 2949, 3231.

Step 1: synthesis of (cis/trans)-(3K)-(1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride (5) (Cis/trans)-(7K)-7-methyl-spiro (4, Anonan-2-one (54) (74bmg, 4.88mmol) was refluxed under Ge in a mixture of 1,4-dioxane (5ml) and 6M NH (15ml). After 4 hours, the mixture was cooled to room temperature, diluted with water ( 20 ml) and washed with dichloromethane (3x 30 ml). The aqueous phase was collected and removed - the solvent under vacuum. The residue was triturated with ethyl acetate and after collection and drying a white solid was obtained. It was recrystallized from a mixture of ethyl acetate/methanol and after collection and drying 65 mg of 6590) (5). "IN NMR 400 MHz, (d6-DMSO): 5 0.96 (ZH, t), 1.01-1.24 (2H, t), 1.42-2.10 (BN, t), 2.41 and 2.44 (2H total, ich- 2 x 8, cis/trans), 2.94 (2H, t), 7.96 (ZH, Bg 5), 12.35 (1H, Bg 5).

Mass spectrometry (ESB) m/e: 172 (M--1 for the free base form).

EXAMPLE 6: (t)-(trans)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride "shi c;" -And 1 1 - 50

Co.)

Ф) име) 60 b5 bok p borv 70 7: - kha n y "7 Y is Zm 5 (be tyu ce ssh shshjo teh i y pysoshchi ns 4 t i 156 iy : - and /no .

Reagents: (i) triethylphosphonoacetate, Ma; (her) Memo", ViaME; (iiii) H",, Mi; (im) NSI rch-

Stage i: synthesis of (cis)-(3,4-dimethyl-cyclopentylidene)-acetic acid ethyl ether (65)

Ma (6095 dispersion in oil, 519mg, 12.96mmol) was suspended in dry tetrahydrofuran (30ml) and cooled to 02. Then triethylphosphonoacetate (2.68ml, 13.35mmol) was added and the mixture was stirred at 02C for 15 minutes. Then (35,4K)-3,4-dimethyl-cyclopentanone (ba) (1.21g, 10.80mmol) in THF (10ml) was added and the mixture was allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 ml) and water (15 ml). The organic phase was separated, washed with saline solution, dried (Mo5O)) and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel, ethylacetate-teptane 5:95) to obtain 1.40 g (71905) (2) in the form of a colorless oil. " "YAN NMR 400MHz, (SOSIv): 5 0.84 (NM, a, 9U-6Gu), 0.91 (ZN, a, 9-6Hutz), 1.26 (ZN, 6, 9-7Hz), 2.01-2.95 (6H, 7 c t), 4.13 (2H, a, 9-7Hz), 5.76 (1H, c). and Mass spectrometry (Sik) m/e: 183 (M'-1) "» IR spectroscopy (film) in cm"!: 1043, 1125, 1200, 1658, 1715, 2959.

Stages: synthesis of (trans)-(3,4-dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ether (bs) (Cys)-(3,4-dimethyl-cyclopentylidene)-acetic acid ethyl ether (65) (1.384g, 7.b0mmol) was dissolved in tetrahydrofuran (10ml) and mixed at 709С with nitromethane (0.82ml, 15.2mmol) and sl tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 11.4ml, 11.4mmol). After b hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50ml) and washed with 2M HCl (30ml) and then with saline solution 1 (50ml). The organic phase was collected, dried (М950О0.5) and the solvent was removed under vacuum. The residue was purified by -1 50 flash chromatography (silica gel, ethylacetate-teptane 5:95) to obtain 0.837g (4595) of a clear oil.

TN NMR 400 MHz, (SOS): 5 0.91 (6M, a, U-6HzC), 1.21-1.39 (5H, t), 1.98 (2H, t), 2.18 (2H, t), 2.64 (2H, g» 8 ), 4.15 (2H, a, 9-7Gu), 4.61 (2H, 5).

Mass spectrometry (EB'K) m/e: 244 (M'-1)

IR spectroscopy (film) in cm"!: 1184, 1377, 1548, 1732, 2961.

Her stage: synthesis of (trans)-7,8-dimethyl-spiro(4,nonan-2-one (ba)

HF) (trans)-(3,4-dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ether (bs) (0.83 g, 3.4 mmol) was dissolved in methanol (30 ml) and shaken over a Raney nickel catalyst in a hydrogen atmosphere (4Orzi) at 3026.

After 4 hours, the catalyst was removed by filtration through Celite. The solvent was removed under vacuum to give 567 mg (9995) of a pale yellow oil which solidified later. 60 TN NMR 400MHz, (SOSIz): 5 0.89 (BM, a, U-6Gu), 1.38 (2H, t), 1.91 (2H, t), 2.10 (2H, t), 2.32 (2H, c), 3.18 (2H, 5), 5.61 (1 H, Bg 5).

Mass spectrometry (EBu) m/e: 168 (M'-1)

IR spectroscopy (film) in cm"1: 1304, 1450, 1699, 2871, 3186. 65 Stage im: synthesis of (trans)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride (6) (Trans)-7,8-dimethyl-spiro(4,nonan-2-one (ba) (56 mg, 4.40 mmol) was refluxed in a mixture of 1,4-dioxane (bml) and 6M HCl (15 ml) After 4 hours, the mixture was cooled to room temperature, diluted with water (20 mL) and washed with dichloromethane (3 x 30 mL). The aqueous phase was collected and the solvent was removed under vacuum. The residue was triturated with ethyl acetate and after collection and drying, a white solid was obtained.

It was recrystallized from ethyl acetate/methanol and after collection and drying gave 440 mg (5996) (6).

TN nMR 400MHz, (d6-DMSO): δ 0.84 (6H, a, 9-6Hz), 1.21 (2H, t), 1.81 (2H, t), 2.06 (2H, t), 2.47 (2H, 8), 2.89 (2H, in), 7.94 (ZN, brg in) 12.30 (1H, Bg 5).

Mass spectrometry (ESB) m/e: 186 (M.--1 for the free base form).

EXAMPLE 7 (w)-(trans)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride

I M Mrs. KU te o e p si y shina SHIA "IT is one you g. z / i: y 7 -a "Z y y y 5 Ge zo y y dy ty y pi m

It is the same in AK shih M and 4 the same:

Reagents: (i) triethylphosphonoacetate, Ma; (iii) Memo", VIM; (iiii) No, Mi; (im) NSI (35,45)-3,4-Dimethyl-cyclopentanone (7a) is described in the literature and can be synthesized by the method described in: U. Kaio, Spet. RNagt. Viii., 1966; 14:1438-1439 and in the references related to this publication: From mm sms. KokKe, RG.A/ MagKemivzeg, U. Ogd. Spet., 1974;39:1535; K. VaKeg, O. ViShpdp, M. EgapauaKe, Usz5 s Spet. Sott., 1981:1234; K. Rigshia, K. Imapada, N. Matatoiyo, Thei. Gen., 1986; 27:4507; 0. Boyiadie, O. Ionze, "from Tei Avutt., 199354:1547; A. Kozepdivi, I. Kmagpvigot, 5.S.T. Zmepezzop, V. Siazzop, V. ZatieiYvvop, Asia

Spent Zsapa., 1992; 46:1127; IS.). Sogeu, MU. Yes, Tei. Yey, 198:29:3423; OHM/. Kpidni V. O|paga, Tei. g., 1981; 22:51011. - 45 Stage i: synthesis of (trans)-(3,4-dimethyl-cyclopentylidene)-acetic acid ethyl ether (76)

To a suspension of sodium hydride (1.3g, 32.5mmol) in THF (bOml) in a nitrogen atmosphere at 09C was added (9) triethylphosphonoacetate (6b.5ml, 32.7mMol) for 5 minutes. After stirring for another 10 minutes, a solution of (33,48)-3,4-dimethylcyclopentanone (7a) (about 2.68Hg, about ZOmmol) in THF (2 x 10ml) was added to the now clear solution and the ice bath was removed. After 4 hours, the reaction was quenched by pouring the mixture into water (100 ml), then extracted with ether (400 ml). The organic phase was washed with a saturated saline solution

Kz (10 Oml), dried and concentrated under vacuum. After column chromatography (10:11 heptane/ethyl acetate) the product was obtained as an oil (4.53g) (yield approx. 91906).

TN NMR 400MHz, (SOSIv): 85 1.01 (ZM, a, 9-6Hz), 1.03 (ZN, a, 9-6Hz), 1.26 (ZN, 5, 9U-7Hz), 1.49 (2H, t), vv 207 (1H, t), 2.24 (IN, t), 2.61 (1H, t), 4.13 (2H, a, U-7Hz), 5.72 (1H, 8).

Mass spectrometry (Sik) m/e: 183 (M'-1)

F) Stages: synthesis of (trans)-(3,4-dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ether (7c) to a solution of (trans)-(3,4-dimethyl-cyclopentylidene)-acetic acid of ethyl ether (75) (4.24 g, 23.3 mmol) in THF (15 ml) was added TVAE (32 ml of a 1M solution in THF, 32 mmol) and then nitromethane (3 ml), after which the reaction was maintained for 8 hours at a temperature of 6022. After cooling, the reaction mixture diluted with ethyl acetate (150ml) and washed with 2M HCl (40ml) and then saturated saline (500ml). After column chromatography (10:1 heptane/ethyl acetate), the product was obtained as an oil (2.24 g) (yield 4096). "H NMR 400MHz, (SOSIv): 5 0.98 (BM, a, U-6Hz), 1.10-1.39 (BN, t), 1.47 (2H, t), 1.87 (1H, t), 2.03 (1H, t) . 244 (M'-1)

IR spectroscopy (film) in cm"!: 1186, 1376, 1549, 1732, 2956.

Stage 1: synthesis of (i)-(trans)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride (7)

A solution of (trans)-(3,4-dimethyl-1-nitromethyl-cyclopentyl)-acetic acid ethyl ether (7c) (3.5 g, 14.4 mmol) in methanol (10 Oml) in the presence of a nickel sponge was hydrogenated at 302 and 5 Orv for 4 hours . The catalyst was filtered off and the filtrate was concentrated under vacuum to obtain a 2:11 mixture of lactam and amino ester, 2.53 g of 9695, which was further used without purification. This mixture (2.53g, 13.8mmol) in dioxane (15ml) and EM NOI (45ml) was refluxed (1102 in an oil bath) for 4 hours. After cooling and diluting with water (bOml), the mixture was washed with dichloromethane (3x 5Oml) and then concentrated under vacuum.

The obtained oil was washed with ethyl acetate, then with dichloromethane to obtain a sticky foam, which was dried at 70 to obtain the product in the form of a white powder (2.32 g) (yield 7690). and. 0(2323ХН2О)(с-1.002)-28.29 "NN nMR 400MHz, (45-DMSO): 5 0.91 (6Н, а, 9-6Hz), 1.18 (2Н, т), 1.42 (2Н, т), 1.72 ( IN, t), 1.87 (1Н, t), 2.42 (2Н, АВа, 9-16, 24Hz), 2.90 (2Н, АВа, 9-12, 34Hz), 8.00 (ЗН, bБгв), 12.34(1 Н, rgv).

Mass spectrometry (EBU) m/e: 186 (M.-1 for the free base form)

EXAMPLE 8 1A,3B,58-(1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride o. I 0 0p5OEV sh t

D tsa eh 48 "85 ate o what Her" in y no. NNa: g" sch se ЧК в ЧЕ y). F 2 F her 84) ibe). Step 1: synthesis of 2-cyano-((ZK,55)-3,5-dimethyl-cyclohexylidene)-acetic acid ethyl ether (86): from

Cis-3,5-dimethylcyclohexanone (8a, 15.78g, 125.0mmol) was dissolved in toluene (150ml) and treated with ammonium acetate (0.96bg, 0.099mmol), acetic acid (1.4ml, 0.195mmol) and ethyl cyanoacetate (14.04g, 99.2mmol). :z» The reaction mixture was refluxed overnight with a Dean-Stark trap, then cooled to room temperature and washed with NaO (3x 50ml). The aqueous layer was washed with toluene (2 x 5 Oml). The organic layers were combined, dried over NaCl, and concentrated. The residue was subjected to chromatography on y y y y -1 silica gel, eluting with 595 EOAc/hexane to obtain 22.0 g (8095) of the required product in the form of a clear oil. 1 Mass spectrometry: 222.1 (Ma-1 for С43Н49М4О»); butter; TLC: Zi", KO.40 (9:11 hexane/EIOAc); Microanalysis of (Si8NluoM102) (calculation) C: 70.56, H: 8.68, M: 6.33 (analysis result) C: 70.74, H: 8.68, M: 6.33. "N NMR

SOSI3) 6: 0.83-0.95 (t, 1Н), 1.01 (6 6Н), 9-6.1ГгФф), 1.32 (Б ЗН, 9У-7.3ГЦС), 1.48-1.85 (t, 5Н), 2.97-3.02 (t , and 1H), 3.92 (ad, 1H, 9-12.2, 2.2 Huz), 4.24 (a, 2H, 2-7.1 Hu). from Stage ii: synthesis of 1TA,3B,58-1-cyanomethyl-3,5-dimethyl-cyclohexanecarbonitrile (8c): 2-Cyano-((ЗК,55)-3,5-dimethyl-cyclohexylidene)-acetic acid ethyl ether (85, 6.64g, 30.OmMmMol) was dissolved in EUN (bOml) and added to a suspension of Masm (1.47g, 30.OmMol) in EUN/H-O (100ml/vml). Reactionary

The mixture was refluxed overnight, then cooled to room temperature, filtered and concentrated under vacuum to give a clear oil which solidified under vacuum. iF) The residue was chromatographed on silica gel, eluting with 4:1 hexane/EtOAc to give 4.05 g (7790) of the required product as a white, sticky solid.

Mass spectrometry: M ion was not observed (C 44Ni6M2); butter; TLC: Zi", KO.31 (4:11 hexane/EUds); 60 Microanalysis (C44Nuivimo) (calculation) C: 74.96, H: 9.15, M: 15.89 (analysis result) C: 74.81, H: 9.25, M: 15.65. /N

NMR (SOCIz) 6 0.58 (4, 1H, 9U-24.9, 12.2HF), 0.96 (a, bH, 9U-6.6Hz), 1.03 (6 2H, 9U-12.9Hsh), 1.75-1.90 (t,

ZN), 2.01 (a, 2H, 9-11.5 HZ), 2.65 (5, 2H).

Stages: synthesis of TA,3B,58-(1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (89): 1A,38B,58-1-cyanomethyl-3,5-dimethyl-cyclohexanecarbonitrile (83 , 5.51g, 31.2bmMol) was dissolved in EUN (8Oml) 65 and toluene (vOml), cooled to 02 and saturated with gaseous NOS. The solution was tightly closed and stirred overnight at room temperature, then concentrated under vacuum to give the crude iminoether as a white solid. This crude material was triturated with EG2O (150ml) and dried under vacuum, then treated with HO (100ml) and 1M HCl (4ml). The reaction mixture was stirred overnight at room temperature, then extracted with EtOAc (3x 100 mL). The organic layers were combined, washed with saline solution, dried over

Ma?zZO, and concentrated. The residue was chromatographed on silica gel, eluting with 6:1 hexane/EtOAc to give 5.78 g (8395) of the required product as a clear oil.

Mass spectrometry: 224.1 (Ma-1 for С43Н214М4О»); butter; TLC: Zi", KO.32 (6:11 hexane/EIOAc); Microanalysis (Siz3No4M405) (calculation) C: 69.92, H: 9.48, M: 6.27 (analysis result) C: 70.03, H: 9.45, M: 6.30. "H NMR (SOSI.) 65 b.5BUaa, M, 9-24.9, 12.0Hz), 0.91 (a, bH, U-6.6Hz), 1.27 (5 ZN, 9U-7.1Hz), 1.70-1.76 (t .

Stage 1: synthesis of 5A,78,9-7,9-dimethyl-2-azo-spiro|4,5|decan-3Z-one (ve) 1A,38B,58-(1-cyano-3,5-dimethyl -cyclohexyl)-acetic acid ethyl ether (8a, 5.82 g, 26.1 mmol) was dissolved in Meon (15 Oml), treated with 1095 KP/290R a/s (1.0 g) and shaken in an atmosphere of H". (5 Orzi) within 28 hours.

The reaction mixture was filtered and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with a 75 gradient of 2:3 hexane/mE(OAc, EIOAc, 596 MeonN/EAOAc) to obtain 2.21 g (4795) of the required product.

Mass spectrometry: 182.0 (Mya-1 for ОО 44Н349М404); For that 116-118927; TSH: Bi", KO.36 (696MeonN/SNosI");

Microanalysis (C44N.l9M4104) (calculation) C: 72.88, H: 10.56, M: 7.73 (analysis result) C: 72.84, H: 10.67, M: 7.63. "H NMR (SOSI") 5 0.49 (dd9, 1H, U-24.4, 12.OGr), 0.86-0.93 (t, 8H), 1.38-1.48 (t, 2H), 1.60-1.71 (t, ZN), 2.09 (in, 2H), 3.16 (in, 2H), 5.79 (Bg, 1H).

Stage M: synthesis of 1A,3B,58-(1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (8):

BA,78,98-7,9-Dimethyl-2-azo-spiro|4,5|decan-3-one (ve, 0.52g, 2.87mmol) was treated with 6bM NH (19ml) and refluxed for at night The reaction mixture was cooled to room temperature, during which a white precipitate was formed. The solid residue was filtered off, and the filtrate was cooled to 02C to induce a second precipitation of crystals, then filtered again. The solid residues were combined and dried under vacuum to obtain 0.46 g (68905) of the required product. at

Mass spectrometry: 200.1 (Ma-1 for С 44Н24М4105); Tdl 179-180; Microanalysis (С44Н24М1О») (calculation) C: 56.04, H: 9.41, M: 5.94 (analysis result) C: 56.16, H: 9.42, M: 5.73. "H NMR (CO3O0) 5: 0.46-0.53 (t, 1H), 0.77 (B TN, 9-12.5HF), 0.85-0.91 (t, 7H), 1.55-1.67 (t, 5H), 2.11 (a, 2H, 9U-13.AHc), 2.36 (in, 2H), 2.44 (in, 1H), 3.14 (in, 2H). Ha

EXAMPLE 9 1A,3B,58-(3,5-dimethyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride: M no

That Shk and 7 U and . cit sec -

SA KI; I'm still there. her "riv p no NYA - i kk x « y" toy - s -5 Я » -I t Я 1 1А,38,58-(1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (8 . ), and shaken in an atmosphere of H" (5 Org) for 3 hours. The reaction mixture was filtered, treated with NCI/ESO (1M, 10ml) and concentrated under vacuum. The crude product was recrystallized from II-RHOH/acetone/hexane (14:200:225ml) and dried under vacuum to obtain 0.136g (12905) of the required product.

Mass spectrometry: 242.1 (Ma-1 for C 44N27M4052); Tdl 178-1802C; Microanalysis (С44Н27М4О».NSI.0.27. NEW) (calculated) C: 59.48, H: 10.18, M: 4.95 (analysis result) C: 59.53, H: 10.21, M: 4.78. "H NMR (СО50О0) 5 0.52 (aa, tn, 9U-24.2, 12.0Gy), 0.83-0.90 (t, 8Н), 1.00 (B ЗН, 9-7.6Hz), 1.61-1.80 (t, 7Н), 2.43 (in, 2H), 2.98 (i,

F) 2H, 4-7.8 Hz), 3.20 (in, 2H). ka EXAMPLE 10 1A,3B,58-(1-ethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride 60 b5 y TI ZT - t E, p ee

S and

The compound of example 10 was synthesized by the method of example 9, except that instead of propionaldehyde, acetaldehyde was used, and ethyl acetate/heptane was used for recrystallization (yield 30905).

Mass spectrometry: 228 (Ma1 for C 45NoeM105); Tll 188-190; "H NMR (DMSO) 5: 0.83 (8Н, Bg a), 1.24 (ЗН, и, 92-7.1Гу), 1.60 (ЕН, т), 2.38 (и, 5), 2.98 (2Н, т), 3.10 (2H, Bg 5), 8.33 (2H, bBgv), 12.42(1H, bgv).

EXAMPLE 11 1A,3B,58-(1-benzylamino-methyl)-3,5-dimethyl-cyclohexyl-acetic acid hydrochloride:

STILL oh! d more 4. SHCI i m

Compound of Example 11 was synthesized by the method of Example 9, except that benzaldehyde was used instead of propionaldehyde, and ESO was used for recrystallization (yield 30905). from Mass spectrometry: 290.1 (M-1 for С 48Н27М4О052); Tll 162-1632C; Microanalysis (Si8H27M1O»-HCI.0.20 NEW) (calculation) C: 65.62, H: 8.69, M: 4.25 (analysis result) C: 65.60, H: 8.71, M: 4.31. "H NMR (SOZOO) 5 0.48 (av, 1H, 9-12.5Her), 0.79-0.90 (t, 8H), 1.46 (p, 2H), 1.64 (a, ЗН, 9-13.4Hz), 2.42 (in . )-acetic acid hydrochloride: 1

AK. everything

F) EE in SH 65 Solution of 1A,38,58-(1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (8, 0.20g, 0.59MmMol) in EUN (15ml), sodium hydroxide (1M . The reaction mixture was then filtered, treated with 1M HCl/EG20O (ml) and concentrated under vacuum. The residue was dissolved in hot iso-PrOH (4 ml), diluted with acetone (100 ml) and

ESO (Z35Oml) and cooled to 02С. The solid residue was filtered off and dried under vacuum to give

LOZmg (exit 7095) of the required product.

Mass spectrometry: 228.1 (Ma-1 for С42Н23М40»2); Tll 195-1962C; Microanalysis (С42Н2зМ4О».НС0.41 НХО) (calculated) C: 57.58, H: 9.97, M: 5.16 (analysis result) C: 57.73, H: 9.71, M: 4.91. "H NMR (СО500) 5: 0.56 (aa, 1H, 9U-24.4, 12.ОГо), 0.89-0.92 (t, 8H), 1.59-1.75 (t, 8H), 2.51 (v, 2H), 2.95 ( c, BN), 3.44 (c, 2H).

EXAMPLE 13 1A,3B,58-(1-butylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride: -

This one is connected (8)

The compound of example 13 was synthesized by the method of example 9, except that instead of propionic aldehyde, butyric aldehyde (yield 489605) was used.

Mass spectrometry: 256.1 (М--1 for C 45Н29М4105); Tll 184-1852C; Microanalysis (Си5НооМ10».NSІ). (calculation) c zo C: 81.73, H: 10.36, M: 4.80 (analysis result) C: 61.71, H: 10.21, M: 4.72./Н NMR (СО3О0) 5: 0.53 (ad, 1Н,

U 24.4, 12.0GF), 0.86-0.99 (t, 11), 1.37-1.47 (t, 2H), 1.60-1.75 (t, 7H), 2.43 (v, 2H), 3.02 (B 2H, - uUE8.1Gu ), 3.20 (c, 2H). iv)

EXAMPLE 14 1A,3B,58-11-Kbenzylmethylamino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid and hydrochloride: m.

Z child U Shcho ke IY y lyoh I : ey Eli y shsh 7. o y Z Zh. - y yiv. with her

Y min g. Y - ; sl -

OO

- 50 that) The compound of example 14 was synthesized by the method of example 9, except that M-benzyl analog (11) and formaldehyde were used as starting materials, and Ri" was used as a catalyst instead of Ra/C (yield 7096).

Mass spectrometry: 304.1 (Mya-1 for С49Но9М105); Tdl 209-2102C; Microanalysis (С19НооМ10».НСИ.0.21Н50)

F! (calculation) C: 66.40, H: 8.92 M: 4.08 (analysis result) C: 66.40, H: 9.05, M: 4.06."H NMR (SOZOB) 5: 0.51 (ad, with 1H, 9u-24.4, 12.0ГФф ), 0.79-0.92 (t, 9H), 1.29 (rg, 1H), 1.56-1.82 (t, 4H), 2.51 (aa, 2H, U-18.8, 16.3Hz), 2.85 (5, 2H), 3.23- 3.49 (t, 2H), 4.37 (a4d, 2H, 9U-31.7, 12.7Gu), 7.45-7.54 (t, 5H).

EXAMPLE 15 1A,38,58-(3,5-dimethyl-1-methylaminomethyl-cyclohexyl)-acetic acid hydrochloride: 60 b5

And g; ; p and paradise

The compound of example 14 (0.14 g, 1.21 mmol) was dissolved in 9595 EN (5 Oml), treated with a solution of 20 sodium hydroxide (1 M, 1.21 mmol) and 2095 Ra/C (0.1 g) and shaken in an atmosphere of NO (5 Org) for 45 minutes. The reaction mixture was then filtered, treated with 1M HCl/EBO (1M, Tml) and concentrated under vacuum. The residue was treated with hot i-RION, Mas! was filtered, and the solution was concentrated under vacuum. The crude product was recrystallized from i-RION/acetone/hexane (7:150:110ml) and dried under vacuum to obtain 0.18g (6390) 25 of the required product. high school

Mass spectrometry: 214.1 (М--1 for C 412Н2з3М4О»5); Tpl. 182-1832C; Microanalysis (С12Но3М1О5-НСИ) (calculated (СО

C: 57.70, H: 9.68, M: 5.61 (result of analysis) C: 57.47, H: 9.58, M: 5.35." H NMR (CO8O0) δ: 0.52 (ad, 1H, 9-24.4, 12.2Ho), 0.84 -0.98 (t, 8H), 1.57-1.72 (t, 5H), 2.38 (c, 2H), 2.72 (8, ЗН), 3.21 (c, 2H).

EXAMPLE 16 1A,3B,58-(1-(acetylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid: c 30 - m ! iv) oz. And I'm 70 years old: " ;» ak and I -I

The compound of example 8 (0.5 g, 2.1 mmol) was treated with HO (1 ml) and Mahon (0.56 g, 14.0 mmol), cooled to 02 o and treated with acetic anhydride. The reaction mixture was stirred at room temperature, then diluted with EtOAc (100 mL) and washed with 1 M NOSI (100 mL). The organic layer was dried over NaCl and concentrated under vacuum. -I 50 The crude material was chromatographed on silica gel, eluting with 495 Meon/SnHSiIi» to obtain 0.138 g (2790) of the required product as an oil, which solidified under vacuum. kz Mass spectrometry: 242.1 (Ma-1 for C 43NozM1052); Tdl. 122-1242C; Microanalysis (С43Н2зМ1О") (calculation) C: 64.70 H: 9.61, M: 5.80 (analysis result) C: 64.65, H: 9.59, M: 5.63." H NMR (СО5О0) 5 0.46 (ad, 1M, uU-23.7 . (c, ZN). 29 EXAMPLE 17 1A,z3B,58-(1-(isobutylamino-methyl)-3,5-dimethyl-cyclohexyl/|-acetic acid hydrochloride:

F) name) 60 b5

70th what child, cha Y .

The compound of example 17 was synthesized by the method of example 9, except that instead of propionic aldehyde, isobutyric aldehyde was used (yield 53905).

Mass spectrometry: 256 (Ma1 for С45Но9М102); Tll 193-194; "H NMR (CO3O0) 5 0.53 (ad, 1H, 9U-24.3, h 12.5HF), 0.81-0.90 (t, 2H), 0.89 (y, 6H, 9-6.4Hz), 1.03 (a, bH, U -6.8Hz), 1.57-1.71 (t, 5H), 2.09 (t, 1H), 2.49 (v, 2H), 2.88 (a, 2H, 9-7.1Gu), 3.19 (v, 2H).

EXAMPLE 18 1A,3B,58-I3,5-dimethyl-1-(phenethylamino-methyl)-cyclohexyl|-acetic acid hydrochloride: 25.

From x to: EE h- p. ! y - du The compound of example 18 was synthesized by the method of example 9, except that instead of propionic aldehyde - phenylacetaldehyde was used (yield 16905). c Mass spectrometry: 304 (M-1 for С 419Но9М40»5); Tll 188-189; Microanalysis (C49NooM4O». NOI) (calculation) :z» C: 67.14 H: 8.90, M: 4.12 (analysis result) C: 66.94, H: 8.91, M: 3.98. "H NMR (СО5О0) 5: 0.46 (ad, 1M, 9-24.6, 12.3Hz), 0.81-0.91 (t, 8H), 1.58-1.72 (t, 5H), 2.50 (in, 2H), 3.04-3.08 (t, 2H), 3.26-3.30 (t, 4H), 7.23-7.75 (t, 5H).

EXAMPLE 19 1A,38,58-13,5-dimethyl-1-((3-phenyl-propylamino)-methyl|-cyclohexyl|-acetic acid-I hydrochloride: 1 more « I rya IH. and 2. . I I with

GF) pok kn -

The compound of example 19 was synthesized by the method of example 9, except that instead of propionic aldehyde, hydrocinnamic aldehyde (yield 50905) was used. 65 Mass spectrometry: 318 (М--1 for С 20Н31М40»); Tll. 171-172; Microanalysis (С2оНзиМ4О». NOI) (calculation)

C: 67.87 H: 9.11, M: 3.96 (analysis result) C: 67.83, H: 9.13, M: 3.78. "H NMR (СО5О0) 5 0.53 (44, 1M, U-24.6,

12.1Hz), 0.80-0.90 (t, 2H), 0.90 (a, 6H, 9U-6.0Hz), 1.60-1.72 (t, 5H), 2.03-2.11 (t, 2H), 2.45 (v, 2H), 2.73 (6 2H, 9-7.5Hz) b 3.06 (Yu, 2H, 9-7.7Hz), 3.3 (v, 2H), 7.20-7.18 (t, 5H).

EXAMPLE 20 /1-(cyclobutylmethyl-amino)-methyl/|-cyclohexyl)-acetic acid hydrochloride:

IN

70 pi pii 4 "e Kai i, p b what t

The compound of example 20 was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, cyclobutanone was used (yield 7090).

Mass spectrometry: 226 (M-1 for С413Н23М4О0»); Tll 176-1779C; Microanalysis (С43Н»з3М4О». NOI) (calculation) sch

C: 59.64 H: 9.24, M: 5.35 (analysis result) C: 59.88, H: 9.18, M: 5.19. "H NMR (СО5О0) 5: 1.16-1.60 (re, 10M), 1.80-1.96 (t, 2H), 2.21-2.40 (t, 4H), 2.53 (b, 2H), 2.97 (b, 2H), 3.73 (t, 1H).

EXAMPLE 21 1A,3B,58-(1-isopropylamino-methyl)-3,5-dimethyl-cyclohexyl|-acetic acid hydrochloride:

KE. with 30 what in sh 1 : yuyu that Vk Z M. ' « t Z shi p: tv s y, "»

The compound of example 21 was synthesized by the method of example 9, except that instead of propionic aldehyde, acetone was used (yield 50965). g Mass spectrometry: 242 (Mat for С 44Н27М102); Tll 206-207; "H NMR (СО3О0) 5 0.53 (ad, 1Н, у-24.8, 12.5ГФр), 0.80-0.90 (t, 2Н), 0.99 (а, 6Н, 2-6.1Hz), 1.35 (а, бН, 9У- 6.6 Hz), 1.55-1.78 (t, 5H), 2.45 (c, 2H), i-th 3.18 (85, 2H), 3.41 (t, 1H). -I 20 EXAMPLE 22 1-aminomethyl-1-cyclohexane- acetic acid earlier (described in Baigipdeg ei ai. О5 4087544, dated May 2, 19781. o EXAMPLE 23 1-aminomethyl-1-cyclopentane-acetic acid previously | described in 5aigipdeg ei ai. О5 4087544, dated May 2, 19781.

EXAMPLE 24 1-Aminomethyl-1-cyclopentane-acetic acid sodium salt previously (described in Zayipdeg eg a. O5 25 4087544, dated May 2, 1978).

HF) EXAMPLE 25 1-(Hydroxymethyl)cyclohexane-acetic acid sodium salt earlier (described in 5baigipdeg ei ai. yuyu OZ 2960441, 1960).

EXAMPLE 26 Synthesis of 411-((2-methyl-butylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride: 60 б5 ша ЦИ 70 Шо Ж! d

A solution of (1-aminomethyl-1-cyclohexyl)-acetic acid (Example 22, 2.0g, 11.7mmol) in EUN (100ml) was treated with 2-methylbutyric aldehyde (4ml, 35.1mmol) and Ri 5 (0.5g) and shaken in an atmosphere of No (5 Org) for 2 hours. The reaction mixture was filtered, treated with 1M HCl/EH2O (12ml), concentrated under vacuum, and then dissolved in hot I-HOH (1Oml), diluted with acetone (b0Oml), cooled to 0 C and filtered to obtain 1.58g (4995) of the required product .

Mass spectrometry: 242 (Ma-1 for С 44Н27М4105); Tll 1162-1632; Microanalysis (С4144Н27М41О») (calculation) C: 60.52 H: 10.16 M: 5.04 (analysis result) C: 60.41, H: 10.26, M: 4.95. "H NMR (СО8О0) 5: 0.95 (y, ZM, 9U-7.3Hz), s 1.02 (y, ZN, 9U-6.6Hz), 1.20-1.31 (t, 1H), 1.42-1.56 (t, 11H) . 2H, 9-25.6, 12.9Hz).

EXAMPLE (27) 11-(4,4,4-trifluoro-butylamino)-methyl|-cyclohexyl-acetic acid hydrochloride was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, 4-trifluorobutyric aldehyde was used (yield 19965) Ge

Mass spectrometry: 282.1 (M.-1 for C 413N22M4O2Ez); Tll 163-1642C; Microanalysis (С43Но2М4О2Рз. NSI. 0.058550) k (calculation) C: 49.00 H: 7.31, M: 4.40 (analysis result) C: 48.60, H: 7.29, M: 4.19. "H NMR (СО3О0) 5: 1.40-1.54 (t, 11M), 1.96-2.04 (t, 2H), 2.2-6-2.38 (t, 2H), 2.57 (v, 2H), 3.09-3.13 (t, 4H).iv)

EXAMPLE 28 (1-ethylaminomethyl-cyclohexyl)-acetic acid hydrochloride

DCS y- both M shi "

And I - g" c. y y -y y 1

The compound of example 28 was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, acetaldehyde was used (yield ZO9b). from Mass spectrometry: 200.1 (М--1 for С 44Н24М405); Tld. 160-1662C; Microanalysis (C44 On M10". NS) (calculation)

C: 56.04 H: 9.41, M: 5.94 (analysis result) C: 55.98, H: 9.36, M: 5.79. "H NMR (СО5О0) 5 1.31-1.54 (t, 13M), 2.54-2.56 (t, 2H), 3.06-3.13 (t, 4M). oo EXAMPLE 29 11-(cyclopropylmethyl-amino)-methyl|-cyclohexyl) -acetic acid hydrochloride

F) name) 60 b5

70' shi

F

The compound of example 29 was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, cyclopropanecarboxyaldehyde was used (yield 6290).

Mass spectrometry: 226 (M-1 for С413Н23М4О0»); Tll 177-178; Microanalysis (С43Н»зМ4О». NOI) (calculation)

C: 59.64 H: 9.24, M: 5.35 (result of analysis) C: 59.72, H: 9.15, M: 5.27. "H NMR (СО5О0) 5: 0.50-0.56 (t, 2H), 0.71-0.746 (t, 2H), 1.05-1.30 (t, 1M), 1.42-1.54 (t, 1OH), 2.52 (v, 2H) , 2.94 (a, 2H, 9U-7.3Hz), 3.10 (c, 2H).

EXAMPLE 30 41-(2-Hydroxy-1-methyl-ethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride: with what "HCB. at)

NE KE: ish rani zo : Ya. m s She yu k o

F | m.

Is that "

The compound of example 30 was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, 1-hydroxy-2-propanone was used (yield 6095). in c Mass spectrometry: 230 (M.-1 for С 412Н23М10»5); Tdl 164-1659S; Microanalysis (С434Н23М4О». NS) (calculation) :z» C: 54.23 H: 9.10, M: 5.27 (analysis result) C: 54.23, H: 9.01, M: 5.18. "H NMR (СО5О0) 5 1.30-1.32 (t, ZM), 1.44-1.55 (t, 1OM), 2.60 (v, 2H), 3.11 (t, 2H), 3.28 (rg., 2H), 3.37 (Bg ., 1H), 3.57-3.61 (t, 1H), 3.78-3.81 (t, 1H). 15 EXAMPLE 31 |1-(isobutylamino-methyl)-cyclohexyl/|-acetic acid hydrochloride:

Foooyayy va ХОВ: -i 50 Ж и ше Not LY with us and scha a

I "V K-a 7 55 CE ai o | V stand

The compound of example 31 was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, cyclopropanecarboxyaldehyde was used (yield 3590).

Mass spectrometry: 228 (M--1 for С43Но5М105); Tll 175-1762S; Microanalysis (С413Н25М1О0». NS) (calculation)

C: 59.19 H: 9.93, M: 5.51 (result of analysis) C: 59.28, H: 9.98, M: 5.24. "H NMR (SOZOO) 5 1.03 (a, 6H, 6.9Ho), bo 1.37-1.60 (t, 1OH), 2.10-2.17 (t, 1H), 2.63 (b, 2H), 2.87 (d, 2H , 9-7. AGC), 3.07 (in, 2H).

EXAMPLE 32 (1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride: 70 g

The compound of example 32 was synthesized by the method of example 26, except that propionic aldehyde was used instead of 2-methylbutyric aldehyde.

Mass spectrometry: 214.1 (M-1 for С432НозМ1О2. ); Tdl 174-1772C; Microanalysis (С42Н23М4О». NOI) (calculated) C: 57.70 H: 9.69, M: 5.61 (analysis result) C: 57.55, H: 9.77, M: 5.48. "H NMR (СО35О0) 5: 0.93 (Her, 1M, uU-6.3Hz), 0.99-1.03 (t, 4H), 1.40-1.54 (t, 13H), 1.72-1.78 (t, 2H), 2.96-3.29 (t, 2H).

EXAMPLE 33 |P1-(isopropylamino-methyl)-cyclohexyl|-acetic acid hydrochloride:

What shk o

I know it. In the city

Not even river ke; her And c) zv sh with "

The compound of example 33 was synthesized by the method of example 26, except that instead of 2-methylbutyric aldehyde, acetone was used. from Mass spectrometry: 214.1 (Ma1 for С 12Н23М41О»5); Tll. 193-1942C; "H NMR (SOZOB) 5 1.29-1.57 (t, 18H), 2.59 (5, 2H), 3.07 (v, 2H), 3.38-3.42 (t, 1H). 15 EXAMPLE 34 (1-cyclohexylaminomethyl-cyclohexyl)- acetic acid hydrochloride: -i kt Shchy "g tTyai (9! go Zhe. a o) : ra What in m i ; ik l

The compound of example 34 was synthesized by the method of example 26, except that cyclohexanone was used instead of 2-methylbutyric aldehyde (yield 48905).

Mass spectrometry: 254 (М--1 for С 45Н27М4105); Tll. 198-199922; Microanalysis (С415Н27М1О0». NS) (calculation) because C: 62.12 H: 9.74, M: 4.83 (analysis result) C: 62.18, H: 9.84, M: 4.75. "H NMR (СО5О0) 5: 1.20-1.60 (t, 16M),

1.63-1.76 (t, 1H), 1.88 (Bg., 2H), 2.13 (Bg., 2H), 2.60 (t., 2H), 3.09 (t., ЗН).

EXAMPLE 35 |1-(benzylamino-methyl)-cyclohexyl|-acetic acid hydrochloride: thesis. with di I as ii with ЧИ --ХН: with ; post still -SHKKH and that TYA. 7.

The compound of example 35 was synthesized by the method of example 26, except that benzaldehyde was used instead of 2-methylbutyric aldehyde.

Mass spectrometry: 262.0 (M1 for Сх6НозМ1О»2); You. 125-1352C; "H NMR (СО3О0) 5: 1.38-1.49 (t, 11M), 2.55 (8, 2H), 3.07 (b, 2H), 4.23 (b, 2H), 7.43-7.49 (t, 5H).

EXAMPLE 36 ((1K,ZK)-3-methyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride: c

J: Greek from her

I am the God of heaven and I am you

A b he i- i o vo h 7 i. - (1K,3K)-1-aminomethyl-3-methyl-cyclohexyl)-acetic acid hydrochloride (Example 1, 1.1g, 4.9mmol) was dissolved in ethanol (95ml) and treated with 1M Mahon (5ml). Propionic aldehyde (4.9 Uml) and then 1095 Ra/C (0.5 g) were added, after which the reaction mixture was shaken in an atmosphere of H 5 (5 Org) for 15.75 hours. The reaction mixture was filtered, 1M HCl (20 ml) in ether was added, after which the solution was concentrated under vacuum. The residue -I was dissolved in hot isopropanol (10 Oml), filtered and concentrated under vacuum. Then the residue was dissolved in isolropanol (1 Oml) and recrystallized from acetone. The solid phase was filtered off and the filtrate was cooled overnight, achieving secondary precipitation of crystals. The solid residues were combined to give the required product (0.78g, 6690).

Mass spectrometry: 228.1 (MAT for С 413Н25МО»); Tdl 179-179.52C; Microanalysis (С43Н25МО». NS) (calculation) and C: 59.19 H: 9.93, M: 5.31 (analysis result) C: 59.27, H: 9.97, M: 5.07. IR spectroscopy (KVh, cm"): 2929 (Bg),

Ko) 1717, 1188. "H NMR (СО5О0) 5: 0.84-1.03 (t, 8M), 1.12-1.17 (t, 1M), 1.46-1.79 (t, 8H), 2.43 (z, 2H), 3.00 ( B 2H, 2-7.8Gu), 3.22 (in, 2H).

EXAMPLE 37 11-(cyclopentylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride:

F) name) 60 b5

(and "oh

MORE t. 7 tah yu Ya an y y - | MA 7: Shn. (1-aminomethyl-cyclohexyl)-acetic acid (3.0 g, 17.5 mmol) was dissolved in ethanol (45 ml). Cyclopentanecarbaldehyde (ml, Zeq.) was added and the reaction mixture was treated with Rio (0.25g). Then the reaction mixture was shaken in an atmosphere of NO (5 Org) for 16.5 hours. The reaction mixture was filtered, 1M HCl (20 ml) in ether was added, and then the solution was concentrated under vacuum. Then the residue was recrystallized from hot isopropanol and acetone to obtain the required product (2.32 g, 5290). high school

Mass spectrometry: 254.1 (М--1 for C 415Но7 МО»); Tpd 172-1732S; Microanalysis (С45Но7МО».НСИ) (calculated С: СО 62.16 Н: 9.74, М: 4.83 (analysis result) С: 61.92, Н: 9.88, М: 4.86. IR-spectroscopy (KVh, cm"): 2930, 2854, 2509, 1689, 1455, 1211./H NMR (СО5О0) 5: 1.23-1.32 (t, 2H), 1.41-1.73 (t, 16M), 1.90 (t, 1H), 2.63 (in, 2H), 3.01 ( a, 2H, U-7.6Hz), 3.09 (c, 2H). He

EXAMPLE 38 11-(cyclohexylmethyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride: m : iv) v y

Kd: "from Y ch gofra 415 J she. (1-aminomethyl-cyclohexyl)-acetic acid (3.0 g, 17.5 mmol) was dissolved in ethanol (45 ml). Cyclohexanecarbaldehyde (bBml, Zeq.) was added and the reaction mixture was treated with (0.25g). Then the reaction mixture was shaken in an atmosphere of NO (5 Org) for 16.5 hours. The reaction mixture was filtered, 1M HC (20ml) in ether was added, after which the solution was concentrated under vacuum. Then the residue was recrystallized from hot 59 isopropanol and ether to give of the required product (3.57g, 6790).

HF) Mass spectrometry: 268.1 (MAT for С 415Н57МО5); Tpl 167.5-1682C; Microanalysis (С45Н857МО». NS) (calculation) co C: 63.24 H: 9.95, M: 4.61 (analysis result) C: 63.14, H: 10.01, M: 4.45. IR spectroscopy (KVh, cm"): 2926, 2851, 1718, 1684. "H NMR (СО5О0) 5 1.03 (t, 1M), 1.20-1.85 (t, 20M), 2.63 (in, 2H), 2.88 ( a, 2H, U-6.8Hz), 3.07 (c, 2H). in EXAMPLE 39: (1-(tert-butoxycarbonyl-amino-methyl)-cyclohexyl|-acetic acid: b5

F

(1-aminomethyl-cyclohexyl)-acetic acid (10.0 g, 58.4 mmol) was dissolved in THF (280 ml) and treated with 1 M

Mmaon (128.5 ml). The reaction mixture was cooled to 02C and di-tert-butyl dicarbonate was added in small portions with thorough stirring. The mixtures were allowed to warm to room temperature and stirred overnight. Then THF was evaporated, and the aqueous phase was washed with ethyl acetate (3 x 5 Oml). The aqueous phase was acidified

KNoRO, (44g) and observed foaming. Gradually, the foam turned into a white precipitate. The mixture was stirred for 2 hours, gradually, very slowly, adding KNoRO (1 g). The precipitate was filtered off and washed with water to obtain the required product (15.2 g, 9690).

Mass spectrometry: 272.1 (Ma-1 for С44Но5МО); Tll 181 C; Microanalysis (С14Но5МО)) (calculation) C: 59.52

H: 9.36, M: 4.76 (analysis result) C: 59.51, H: 9.03, M: 4.87. IR spectroscopy (KVg, cm"): 3413, 3054, 2933 (Bg), 1709, 1666, 1531, 1248. "H NMR (СО3О0) 5: 1.03 (t, 1Н), 1.27-1.58 (t, 19Н) , 2.29 (c, 2H), 3.12 (a, 2H, y6.vgHo), 4.97 (b, 1H). high school

EXAMPLE 40: P1-(acetylamino-methyl)-cyclohexyl|- acetic acid and the following VK:

I iv)

3- (1-aminomethyl-cyclohexyl)-acetic acid (2.0 g, 11.7 mmol) was dissolved in HO (20 ml), then Mmaon (3.1 g, 77.B5 mmol, b.v.) and acetic anhydride (1.8 ml) were added , 19.3 mmol, 1.7 eq.). The reaction mixture was left to stir at room temperature for 2 days. Then 1M HCl (125 ml) was added and the reaction mixture was extracted with EtOAc (125 ml). The organic phase was separated, dried over NaClO, and concentrated under vacuum. The residue was dissolved in HO (100 ml), treated with Mahon (0.12 g) and concentrated under vacuum. The sample "» was then subjected to flash chromatography, eluting with Meon/cSnNsi" to obtain the required product (0.31g, 12905).

Mass spectrometry: 214.1 (Ma-1 for С44Н39Моз5); Tdl 107-1082C; Microanalysis (C44Nl9MOz) (calculation) C: - I 61.95 H: 8.98, M: 6.57 (analysis result) C: 61.96, H: 9.03, M: 6.54. TLC: 0.31 b95 Meon/snsi"; sl IR spectroscopy (KVh, cm"): 3286, 3120, 2932, 2440, 1714, 1576, 1419, 1333, 1208. "H NMR (SOSI") 5: 1.25-1.51 (t, TON), 2.06 (in , NM), 2.28 (v, 2H), 3.26-3.29 (t, 2H), 6.32 (rg, 1H). EXAMPLE 41 ((ZK,55)-1-(cyclobutylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride:

And so on

And Fe o sia i: where are you

(ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (0.76 mg, 3.2 mmol) was dissolved in ethanol (45 ml) and treated with 1 M Mahon (3.2 ml). Then, cyclobutanone (ml, bq.) and Ri" (0.2 g) were sequentially added. Then the reaction mixture was shaken in an atmosphere of NO (5 Org) for 16 hours. The reaction mixture was filtered, 1M HCl (ZbBml) in ether was added, after which the solution was concentrated under vacuum. The residue was dissolved in hot isopropanol (15 Oml) and filtered. Then acetone (100ml) and ether (b00ml) were added, which had previously been cooled to 02C. The solution was left at 02С for 2 hours for the formation of crystals. The crystals were collected and washed with ether and acetone (0.38 Hg, 4190).

Mass spectrometry: 254.1 (M-1 for С 415Н57МО»5); Tll. 2000-2012; Microanalysis (С15Н27МО». NS) (calculation) 70. C: 62.16 H: 9.74, M: 4.83 (analysis result) C: 62.09, H: 9.72, M: 4.68. IR spectroscopy (KVh, cm"): 2926, 1720, 1189. "NN NMR (СО5О0) 5: 0.48-0.57 (t, 1Н), 0.85-0.92 (t, 8Н), 1.60-1.73 (t, 5Н) , 1.78-1.93 (t, 2H), 2.22-2.38 (t, 4H), 2.42 (8, 2H), 3.11 (v, 2H), 3.72-3.78 (t, 1H).

EXAMPLE 42 "((3K,55)-3,5-dimethyl-1-(2-methyl-butylamino)-methyl/|-cyclohexyl)-acetic acid hydrochloride:

And I went from Sochi. In (ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (1.0g, 4.4mmol) was dissolved in ethanol (47ml) and treated with 1M Mahon (4.4ml). Then, isobutyric aldehyde (1 ml, Zeq.) and Ri" (0.17) were successively added. Then the reaction mixture was shaken in an atmosphere of NO (5 Orvzi) for 3 hours. The reaction mixture was filtered, 1M HCl (10ml) in ether was added, and then the solution was concentrated under vacuum. The residue was dissolved in hot isopropanol (100 ml) and filtered. It was then concentrated under vacuum and recrystallized from acetone and hexane. The crystals were collected and washed with hexane to obtain the required product (0.89 gH, 7590). at

Mass spectrometry: 270.1 (Mat for C /6Nz1MO"); Tll. 171-173; Microanalysis (С16НзиМО». NOI) (calculated) (U

C: 62.82 H: 10.54, M: 4.58 (analysis result) C: 62.59, H: 10.43, M: 4.52. IR spectroscopy (KVg, cm"): 2964 (Bg), m 1721, 1485, 1186, 840. "H NMR (СО5О0) 5: 0.48-0.57 (t, 1H), 0.81-1.07 (t, 12M), 1.23-1.27 (t, 1H), 1.45-1.72 (t, BM), 1.83-1.91 (t, 1H), 2.50 (v, 2H), 2.83 (aa, 1H, 9U-8.3, 12.5Hz), 3.00 ( aa, 1H, 9-61, 12.5Hz), 3.13-3.29 (t, 4H).

EXAMPLE 43 3(3K.55)-1-K(2-hydroxy-1-methyl-ethylamino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride: « shi | Shk: RAIN

F OK on g t Y: -0.720 : "z e kb, 22 (ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (1.0 g, 4.3 mmol) was dissolved in

Gee! ethanol (45ml) and treated with 1M Mahon (4.3ml). Then 1-hydroxy-propan-2-one (ml, Zeq.) and Rio (0.15 g) were added sequentially. Then the reaction mixture was shaken in an atmosphere of NO (5 Orvzi) for 82 hours. Ri" (0.1 g) and de 1-hydroxy-prolan-2-one (ml) were added, and the reaction mixture was shaken in an atmosphere of H" (5 Orvzi) for 24 hours. The reaction mixture was filtered, 1 M HCl (35 ml) in ether was added, after which the solution was concentrated under vacuum. The residue 60 was dissolved in hot isopropanol (1500 ml) and filtered. It was then concentrated under vacuum and recrystallized from hot isopropanol, acetone, and ether. The crystals were collected and washed with ether and acetone and dried. (0.ZOg, 1.04mmol, 24965).

Mass spectrometry: 258.1 (M-1 for С44Н27МО»z); Tll 178-1799C; Microanalysis (С44Н.7Моз. NS) (calculation)

C: 57.23 H: 9.60, M: 4.77 (analysis result) C: 56.77, H: 9.39, M: 4.45. IR spectroscopy (KVh, cm"): 3349, 2897, bo 1704, 1419, 1194. "H NMR (СО5О0) 5: 0.48-0.57 (t, 1Н), 0.82-0.90 (t, 8Н), 1.25-1.32 (t, 4H), 1.60-1.75 (t,

5H), 2.47 (v, 2H), 3.23 (a, 2H, 2-5.1Hz), 3.38 (t, 1H), 3.58 (ad, 1H, 9U-12.0, 7.1Hz), 3.79 (aa, 1H, 9U -12.0, 4.2Gu).

EXAMPLE 44 (Z3K,55)-1-(2,2-dimethoxy-ethylamino)-methyl|-3,5-dimethyl-cyclohexyl)acetic acid hydrochloride: 7 sino, z s s s s s s s s

NV

(ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (1.0 g, 4.3 mmol) was dissolved in ethanol (47 ml). Then glyoxal 1,1-dimethyl acetal (3.7 ml, 3.Eq.) was added. It was treated with a mixture of Ri" (0.17 g).

Then the reaction mixture was shaken in an atmosphere of NO (5 Org) for 3 hours. The reaction mixture was filtered, 1M HCl in ether (10ml) was added, after which the solution was concentrated under vacuum. The residue was dissolved in hot isopropanol (10 Oml) and filtered. Then the filtrate was concentrated and the residue was recrystallized from acetone and hexane to obtain the required product (0.92 g, 75905).

Mass spectrometry: 288.1 (Ma-1 for С45Н29МОХ); Tll 1252C; Microanalysis (С45НооМО,. НС) (calculation) C: E 55.83 H. 9.34, M: 4.32 (analysis result) C: 55.29, H: 9.48, M: 4.18. IR spectroscopy (KVh, cm"): 2949, 1715, Ge) 1457, 1191, 1134, 1077. "H NMR (СО5О0) 5: 0.47-0.56 (t, 1Н), 0.81-0.90 (t, 8Н), 1.59-1.71 (t, 5H), 2.46 (z, 2H), 3.18 (a, 2M, 9U-5.1, Hz), 3.26-3.29 (t, 2H), 3.45-3.47 (t, 6H), 4.73 (, 1H, 9U-5.1Hz).

EXAMPLE 45 (3K,55)-1-(Cyclopentylmethyl-amino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid with Hydrochloride: more

(ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (1.0 g, 4.1 mmol) was dissolved in ethanol (45 ml) and treated with 1 M Mahon (4.2 ml). Then sequentially added cyclopentanecarbaldehyde (1.5 ml,

Zec) and Pb (0.2g). Then the reaction mixture was shaken in an atmosphere of H" (5 Orvzi) for 12 hours. This is a reaction mixture. was filtered, 1M NSII in ether (Zbml) was added, after which the solution was concentrated under vacuum. The residue was dissolved in hot isopropanol (15 Oml) and filtered. Then the solution was concentrated under vacuum and recrystallized from hot isopropanol, acetone, and ether. The crystals were collected and washed with ether and acetone (0.40 g, 2790). - and 20 Mass spectrometry: 282.1 (Ma-1 for С47Н34МО»); Tll 187-1882C; Microanalysis (С47Н34МО». NS) (calculation) "with C: 64.23 H: 10.15, M: 4.41 (analysis result) C: 64.11, H: 10.04, M: 4.34. IR spectroscopy (KVh, cm): 2952, 1720 , 1452, 1185. "H NMR (CO3O0) 5: 0.48-0.57 (t, 1H), 0.81-0.90 (t, 8H), 1.25-1.32 (t, 2H), 1.60-1.71 (t,

OH), 1.89-1.93 (t, 2H), 2.25-2.29 (t, 1H), 2.49 (v, 2H), 3.01 (a, 2H, 9U-7.6Hz), 3.20 (v, 2H).

EXAMPLE 46 4(3K,55)-1-(cyclohexylmethyl-amino)-methyl|-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride:

Ф) име) 60 b5 not this and what dog what gooply pozheh

(ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (1.0 g, 4.2 mmol) was dissolved in ethanol (45 ml) and treated with 1 M Mahon (4.3 ml). Then, cyclohexanecarbaldehyde (1.5 ml, Zeq.) and Pb (0.15 g) were sequentially added. Then the reaction mixture was shaken in an atmosphere of NO (5 Org) for 17 hours. The reaction mixture was filtered, 1M NaCl in ether (Zbml) was added, after which the solution was concentrated under vacuum. The residue was dissolved in hot isopropanol (15 Oml) and filtered. Then the solution was concentrated under vacuum and recrystallized from hot isopropanol, acetone, and ether. The crystals were collected and washed with ether and acetone (0.46 bg, 3490).

Mass spectrometry: 296.2 (Ma-1 for Сх8Нз3МО»); Tll 176-1772C; Microanalysis (Si8NzzMO". NS) (calculation)

C: 65.13 H: 10.32, M: 4.22 (analysis result) C: 64.89, H: 10.36, M: 4.09. IR spectroscopy (KVh, cm): 2919, 2851, 1721, 1453, 1192. "H NMR (С0О5О0) 5: 0.48-0.57 (t, 1Н), 0.81-0.90 (t, 8Н), 1.00-1.36 (t , 5H), p 29 160-171 (t, 11H), 2.49 (v, 2M), 2.88 (y, 2M, U-6.8Hz), 3.18 (v, 2H). He)

EXAMPLE 47 ((ZK,55)-1-cyclohexylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride: i di s u prp i СХ. GT in I iv) schy 7 MI y y Shen nt. I am in

NO oh, MN: Ov:

FI ":z" (ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (0.99g, 4.2mmol) was dissolved in ethanol (45ml) and treated with 1M Mahon (4.2ml). Then cyclohexanone (1.5 ml, Zeq.) and Ri" (0.27) were added sequentially. Then the reaction mixture was shaken in an atmosphere of NO (5 Org) for 17 hours. The reaction mixture -I was filtered, 1M NaCl in ether (Zbml) was added, after which the solution was concentrated under vacuum. The residue was dissolved in hot isopropanol (15 Oml) and filtered. The solution was then concentrated under vacuum and recrystallized from hot isopropanol, acetone, and ether. The crystals were collected and washed with ether and acetone (0.33 g, 2590).

Mass spectrometry: 282.1 (M-1 for С47Н34МО»); Tdl 2109; Microanalysis (S.47Na41MO". NOSI) (calculation) C: and 64.23 H: 10.15, M: 4.41 (analysis result) C: 63.89, H: 9.98, M: 4.33. IR spectroscopy (KVh, cm"): 2921, 1691,

Ko) 1452, 1216. "H NMR (СО5О0) 5: 0.47-0.57 (t, 1Н), 0.82-0.90 (t, 8Н), 1.30-1.46 (t, 5Н), 1.57-1.63 (t, 2Н), 1.69 (a, 4H, U-12.9Hz), 1.86 (a, 2H, 9-12.5Hz), 2.13 (j, 2H, U-10.3Gu), 2.46 (v, 2H), 3.04-3.10 (t, 1H ), 3.21 (c, 2H).

EXAMPLE 48: ((ZK,55)-1-carboxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid pe o b o i ve OH: y y y y She. t p y y v B 5 y v y r B ch y | And me? y Y "k o I y. y y to y y ognya Ka yo.

Stage i: synthesis of (8K,105)-8,10-dimethyl-2,4-dioxo-3-azo-spiro(5,5)undecane-1,5-dicarbonitrile ammonium salt (482): solution of absolute ethanol (40 ml ) was cooled to 09 and saturated with gaseous MH", then treated with cis-3,5-dimethyl-cyclohexanone (5.0 g, 39.62 mmol) and ethyl cyanoacetate (8.4 mL, 79.24 mmol). The flask was tightly closed, allowed to warm to room temperature and stirred overnight. The precipitate was filtered off, washed with EBO and dried under vacuum to obtain 6.04 g (5995) of the required product as a pale colored solid.

Mass spectrometry: 260.1 (M-1 for С44Н47М3О»); Microanalysis (С44Н.47М3О2. МНзовв НО) (calculation) C: 57.55 H: 7.51, M: 19.17 (analysis result) C: 57.67, H: 7.45, M: 19.06. IR spectroscopy (KVh, cm"): 3298, 2954, 70. 2172, 1700, 1575. "H NMR (SOCIz) 5: 0.46-0.50 (t, 1M), 0.82-1.17 (t, 11M), 1.65- 1.98 (t, ZN), 3.58 (yes, 2H, -13.9, 6.8Hz).

Stages: synthesis of the compound of example 48: (85,10K)-8,10-dimethyl-2,4-dioxo-3-azo-spiro|5,5)undecane-1,5-dicarbonitrile (48a, 25.36g, 97.8 mmol) was treated with concentrated NaClO (102 ml) and water (30 ml). The reaction mixture was heated to 1502C for 5 hours, then allowed to cool to room temperature and stirred overnight. The reaction mixture was filtered, the solid phase was collected and dissolved in 1M Mahon. This solution was filtered and the filtrate was acidified with concentrated HCl (4 Oml).

The precipitate was collected and dried overnight under high vacuum. The compound was then dissolved in hot isopropanol (100 mL) and recrystallized from water to give the desired product (13.21 g, 5996).

Mass spectrometry: 229.1 (M-1 for С 42Н2004); Microanalysis (С42Н20О04) (calculation) C: 63.14 H: 8.83, (analysis result) C: 63.36, H: 8.92. IR spectroscopy (KVh, cm"): 2950, 2913, 1698. "H NMR (СбО05300)5 0.40-0.48 (t, 1Н), 0.77-0.85 (t, 8Н), 1.57-1.77 (t, 5Н), 2.41 (c, 2H), 2.56 (c, 2H).

EXAMPLE 49: trans-(ZK,55)-1-hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride ssh she - a

Her cha i V Z SHY r sii z her ashy u s ozh, kod as Ne She ay shi l -

WITH . o) "Stages and and its: synthesis of (cis/trans)-(75,9K)-7,9-dimethyl-2-oxa-spiro-I(4,5|decan-3-one (49a): (I ).Bicarboxylic acid (48, 6.36 bg, 27.9 mmol) was suspended in HO (9 mL), treated with ammonium hydroxide (Zu B mL) and silver nitrate (4.73, 27.9 mmol) and stirred for 20 minutes at at room temperature. The reaction mixture was filtered and the solid residue was stirred three times with HO, then dried under vacuum in the dark for two days 1 at 502 to give 6.41g of the binary silver salt, which was used immediately. (iii). The binary salt of silver (1.24g, 2.81 mmol) was placed in a dark flask, treated with HCl (5 Oml) and iodine (0.72 g, 2.81 mmol) and kept overnight at 752 C. The reaction mixture was filtered, concentrated under vacuum and chromatographed on silica gel, eluting with 4:1 hexane/ECHOAc with the receipt of 0.37 g (7290) of the required product in the form of

GC of light-colored oil (494).

Mass spectrometry: 183.0 (М--1 for C 44Nui80»5); Microanalysis (С44Ну8О20о. О5НО) (calculation) C: 72.13 H: 9.96, (analysis result) C: 71.77, H: 9.69. IR spectroscopy (KVh, cm 7; 3298, 2954, 2172, 1700, 1575, 1450, 1337. "IN NMR (SOSIZ8, -1:1 mixture of cis/trans diastereomers) 5: 0.49-0.59(t, 1Н), . . hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetamide (490 and 49c): lactone (49a, 0.85 g, 4.6 mmol) was dissolved in THF (18 mL), treated with benzylamine (0.6 b1 mL, 5. mmol) and boiled for 60 under reflux for two days. The reaction mixture was cooled to room temperature, diluted with EAs, washed with saturated sodium bicarbonate solution and brine, dried over

Ma»zO, and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 1:1 hexane/(EuAc) to obtain 0.79 g (5995) of the required product as a clear oil (mixture of cis and trans isomers, 495 and 49c).

Mass spectrometry: 290.1 (Ma-1 for С48Н27М4О52): oil; TLC: Bio, Keg0.16 (2:11 hexane/EEHAc) Microanalysis 65 (Si8No;M1O" (calculation) C: 74.70 H: 9.40, M: 4.84 (analysis result) C: 74.41, H: 9.35, M: 4.57 .

Step iM: separation of 490 and 4U9c: a mixture of cis and trans isomers (4965 and 49c) was separated by preparative HPLC (column 318, eluting with a gradient of 60956 CH 3CM/4095 NiO for 5 minutes, then 4590

SNUSM/5596 NoO 35 minutes, all mobile phases included 0.059565 TFO).

Trans-isomer (495): ET-23.600 Ohv., yield 54mg. "H NMR (SOSIa) 5 0.36-0.62 (t, ZM), 0.82 (4, 6H, U-6.3HC), 1.39-1.70 (t, 5H), 2.14 (v, 2H), 2.58 (Bg, 1H) , 3.60 (v, 2H), 4.43 (0, 2H, 2-5.9Hz), 5.97 (Bg, 1H), 7.26-7.37 (t, 5H).

Cis-isomer (49s): ET-25.828 min., yield 87 mg. "H NMR (SOSIv) 5: 0.47-0.56 (t, 1H), 0.65 (i, 2H, 9U-13.2Hz), 0.85 (a, bH, 9U-6.3Hz), 1.47-1.68 (t, 5H), 2.38 (v, 2H), 2.58 (Bg, 1H), 3.40 (v, 2H), 4.45 (a, 2H, -5.9Gu, 6.03 (Bg, 1H), 7.28-7.36 (t, 5H).

Step M: Synthesis of the compound of example 49: the trans isomer of M-benzyl-2-(1-hydroxymethyl-cyclohexyl)-acetamide (496, 170 in 7 mg, 0.303 mmol) was taken after HPLC, dissolved in 5 ml of water and treated with 24 mg of Mahon. The reaction mixture was refluxed for 2 days. Then it was cooled to room temperature, diluted with 1M MAon and extracted with E(Ac. The aqueous phase was acidified with concentrated NOCI (bml), then diluted with 1M HCl and the product was extracted with EtOAc. The organic phase was washed with saline and dried over NaClO). The solution was concentrated to obtain 2Zmg (61905) of the required product.

Mass spectrometry: 201 (Ma-1 for C 44NooO3); "H NMR (СО5О0) 5: 0.48-0.57 (t, 1Н), 0.88-1.00 (t, 8Н), 1.40-1.49 (t, 2Н), 1.68-1.70 (t, ЗМ), 2.28 (в, 2М) , 4.11 (c, 2H).

EXAMPLE 50: cis-((ZK,55)-1-hydroxymethyl-3,5-dimethyl-cyclohexyl-acetic acid hydrochloride)

The cis-isomer of M-benzyl-2-(1-hydroxymethyl-cyclohexyl)-acetamide (49z, 87 mg, 0.303 mmol) was taken after HPLC, dissolved in 5 ml of water and treated with 24 mg of Mahon. The reaction mixture was boiled under reflux for 3 days, then cooled to room temperature, diluted with 1M Mahon and extracted with EAs. The aqueous phase was acidified with concentrated CARRIER (5ml), then diluted with 1M CARRIER and the product was extracted with EtOAc. The organic phase was washed with saline and dried over NaClO). The solution was concentrated to obtain 4 mg (71965) of the required product. at

Mass spectrometry: 201.1 (M-1 for C 44NorO8); "H NMR (СО5О0) 5: 0.48-0.57 (t, 1H), 0.88-0.96 (t, 8M), 1.42-1.50 (t, 2M), 1.59-1.69 (t, ЗН), 2.37 (8, 2H), 3.94 (in, 2H).

EXAMPLE 51: (1-dimethylaminomethyl-cyclohexyl)-acetic acid hydrochloride « ж С и М И чо , И и в как ша и Й OK chen : seman: 1 (1-aminomethyl-cyclohexyl)-acetic acid (0.51g, Z.Ommol) was dissolved in ethanol and formaldehyde was added. but also what . (Zml, 2 eq.). Then 1095 Ra/C (1.bg) was added and the reaction mixture was shaken at room temperature in a hydrogen atmosphere at 760 Torr for 12 hours. The reaction mixture was then treated with HCl until the pH reached approximately 2, after which it was recrystallized from acetone and ether to give 1.62 g (8790) of the required product.

Mass spectrometry: 200.1 (Ma for C 44H24MO); Tdl. 140-1422C; Microanalysis (С44Н24МО») (calculation) C: 52 54.99 H: 9.44, M: 5.83; (analysis result) C: 54.90, H: 9.36, M: 6.22." H NMR (СО35О0) 5 1.42-1.59 (t, 10OM), 2.63

F! (5, 2H), 2.96 (v, 6H), 3.26-3.29 (t, 2H). EXAMPLE 552: (1-Butylaminomethyl-cyclohexyl)-acetic acid hydrochloride 60 b5 and (1-aminomethyl-cyclohexyl)-acetic acid (0.86 g, 5.0 mmol) was dissolved in ethanol (10 Oml) and Ra/cС ( 1095, 0.86g) and butyric aldehyde (1.44g, Zeq.). The reaction mixture was placed in a hydrogen atmosphere at 760 Torr and kept at room temperature until the reaction was complete. Then it was filtered, acidified and concentrated. The residue was dissolved in isopropanol, filtered and recrystallized from acetone and ether to obtain the required product.

Mass spectrometry: 228.1 (Ma-1 for С413Н25МО»); Tll. 142-1542C; Microanalysis (С413Но5МО». NS) (calculation)

C: 59.19 H: 9.93, M: 5.31; (analysis result) C: 58.85, H: 9.86, M: 5.05. "H NMR (СО5О0) 5: 0.98 (i, NM, -7.Hz), 1.39-1.54 (t, 12H), 1.66-1.72 (t, 2H), 2.57 (v, 2H), 3.01 (6, 2H , U-9.3HZ), 3.09 (in, 2H).

EXAMPLE 53: 41-(2,2-dimethoxy-ethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride vz Obuya ozo: (1-aminomethyl-cyclohexyl)-acetic acid (2.0 g, 11.7 mmol) was dissolved in ethanol (10 Oml). Then glyoxal 1,1-dimethylacetal (3.7 ml, Zeq.) was added and the reaction mixture was treated with Rio (0.5 g). The reaction mixture (C) was shaken in an atmosphere of NO (5 Org) for 4 hours. Then it was filtered, 1M NaCl in ether (15 ml) was added and concentrated under vacuum for 3 hours. The residue was recrystallized from hot isopropanol (25 ml) and acetone (700 ml) to obtain 0.44 g (5295) of the required product.

Mass spectrometry: 260.1 (М--1 for C 413Н25МО,); Tll. 128-1299C; Microanalysis (С413Но5МО, H. NS) (calculation)

C: 52.79 H: 8.86, M: 4.74; (analysis result) C: 52.84, H: 8.94, M: 4.67. IR spectroscopy (KVh, cm: 2926, 1693, « 20 1457, 1208, 1087. "H NMR (СО3О0) 5: 1.40-1.55 (t, 10M), 2.60 (in, 2Н), 3.13 (in, 2Н) .

EXAMPLE 54: (1-Methylaminomethyl-cyclohexyl)-acetic acid hydrochloride with specific, I. y - ich - 50 Shk y : then NI 11-KBenzyl-methyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride ( Example 55, 4.1 g, 13.2 mmol) was dissolved in 9595 ethanol (2500 ml). Then 1095 Ra/cС (1 g) was added and the reaction mixture was shaken at room temperature in a hydrogen atmosphere at 760 Torr for 1 hour. Then it was filtered, concentrated and recrystallized from acetone and ether to obtain 2.69 g (9295) of the required product. i) Mass spectrometry: 186.0 (Ma-1 for С40Н49МО»); Tld 158-1622C; Microanalysis (С19Н49МО». NS) (calculation) where С: 53.09 Н: 9.13, М: 6.19; (analysis result) C: 53.14, H: 8.96, M: 6.34. "H NMR (СО5О0) 5: 1.42-1.54 (t, 1ОМ), 2.50-2.53 (t, 2Н), 2.71-2.74 (t, НН), 3.09-3.11 (t, 2Н). bo EXAMPLE 55: 41- (Benzyl-methyl-amino)-methyl|-cyclohexyl)-acetic acid hydrochloride (1-(Benzylamino-methyl)-cyclohexyl|-acetic acid hydrochloride (0.49g, 1.7 mmol) was dissolved in ethanol (45ml) and treated with 1M Mahon (1.8ml). Formaldehyde (1ml, bq.) was added and the mixture was treated with Ri 25 (0.2g).

The reaction mixture was shaken in an atmosphere of NO (5 Org) for 30 hours. Then it was filtered, 1 M NOSI in ether (1 Oml) was added and concentrated under vacuum. 0.31 g (1.14 mmol, 67905) of the required product was obtained.

Mass spectrometry: 274.1 (M-1 for С 47Н25МО»); butter; IR spectroscopy (KVh, cm 7; 3205, 2930, 2261, 1684, 1451, 1198. High-resolution mass spectrometry: (calculation) 276.1963 (analysis result) 276.1973 (M--1 for С47Но5МО»); "H NMR ( СО8О0) 5: 1.33-1.63 (t, 13M), 2.28 (t, 2H), 3.06 (t, 2H), 4.40 (t, 2H), 7.21-7.34 (t, 5H).

EXAMPLE 56: | (1-Aminomethyl-cyclohexyl)-acetic acid (1-aminomethyl-cyclohexyl)-acetic acid (2.0 g, 11.7 mmol) was dissolved in ethanol (10 mL ). Phenyl acetaldehyde (4 ml, Zeq.) was added and the reaction was treated with 1095 Pa/C (0.5 g). The reaction mixture was shaken in an atmosphere of NO (5 Org) for 3 hours. Then it was filtered, 1 M HCl in ether (2 O ml) was added and The residue was recrystallized from hot isopropanol and ether to give 0.15 g (4.1965) of the required product.

Mass spectrometry: 276.1 (М--1 for С47Но5МО»); Tpl 182-1832C; Microanalysis (С47Но5МО». NSI) (calculation) M

Зз5 C: 64.54 H: 8.46, M: 4.43; (analysis result) C: 64.54, H: 8.35, M: 4.34. IR spectroscopy (KVh, cm/U: 2929, 2855, h- 2813, 1693, 1455, 1220. "H NMR (СО3О0) 5: 1.38-1.58 (t, 10M), 2.56 (z, 2Н), 3.01- 3.06 (t, 2H), 3.14 (v, 2H), 3.23-3.29 (t, 2H), 7.21-7.34 (t, 5H).

EXAMPLE 57: 41-(3-phenyl-propylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride

Ka ge - y : ; - (1-aminomethyl-cyclohexyl)-acetic acid (2.0 g, 11.7 mmol) was dissolved in ethanol (10 mL). They added

He 3-phenyl-propionic aldehyde (4.bml, Zeq.) and treated the reaction with 1095 Ra/sС (0.5g). The reaction mixture was shaken in an atmosphere of No (5 Org) for an hour. Then it was filtered, 1M NaCl in ether (20 ml) was added and concentrated under vacuum. The residue was recrystallized from hot isopropanol and ether to obtain 0.46 g (1290) of the required product.

Mass spectrometry: 290.1 (Ma-1 for С 18Н27МО»); Tll 168-16992; Microanalysis (Si18H.; MO». NS) (calculation) i) C: 66.34 H: 8.66, M: 4.40; (analysis result) C: 66.48, H: 8.65, M: 4.17. IR spectroscopy (KVG, cm"): 2932, 2854, ko 1686, 1454, 1217. "H NMR (СО5О0) 5: 1.38-1.58 (t, 10OM), 2.56 (z, 2H), 2.00-2.04 (t , 2H), 2.56 (z, 2M), 2.71 (B 2H, 9-7.6Gu), 3.01-3.08 (t, 4H), 7.21-7.34 (t, 5H). 60 EXAMPLE 58: ((ZK,55)-1-hydroxymethyl-3,5-dimethyl-cyclohexyl)-acetic acid sodium salt b5

70 schi zhk: . (7k,9Kk)-7,9-Dimethyl-2-oxo-spiro|(4,5|decane-Z-one (49a, 1.04g, 5.71mMmol) was dissolved in water (25ml) and treated with Mahon (2.5g) . The reaction mixture was refluxed for 4 hours. Then the solution was cooled to room temperature, washed with BOH and the aqueous phase was concentrated under vacuum to give a solid (8g). The residue was washed with 1M acetic acid and extracted with E(OAc), which was then concentrated .

Mass spectrometry: 199.0 (M-1 for С44Н20Оз); butter; High-resolution mass spectrometry: (calculation) 199.1334 (analysis result) 199.1333 (M-1 for С 14Н20О3з); Tpl»2502S; IR spectroscopy (KVh, cm"): 2953, 2910, 1777, 1706, 1458, 1168, 1012.

EXAMPLE 59: ((ZK,55)-1-ethylaminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride and o. sch y z or OVO N o t. muscles E.. write Ge

I'm still with you

IS) (ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (59a, 0.418g, 1.8mmol.

Compound 59a was obtained according to the method (described in Vguapv, y. Vioogdapis 4: Medisipa! Spetivigu o

GetsCegv, 1997, 7(19), 24811), was dissolved in ethanol (4bml) and treated with 1M Mahon (1.8ml). Then - acetaldehyde (0.Bml, Zeq.) was added and the reaction was treated with Ri" (0.2g). Then the mixture was shaken in an atmosphere of No (5 Org) for an hour. The reaction mixture was filtered, 1M HCl in ether (2 ml) was added and concentrated under vacuum. The residue was dissolved in hot isopropanol (10 Oml) and filtered. Hexane (100 ml) was added to the filtrate at 0 °C and the precipitate was collected to obtain 31 mg (0.14 mmol, 8905) of the required product.

Mass spectrometry: 228.1 (Ma-1 for С43Но5МО»); Tll 167-1682S; IR spectroscopy (KVg, cm 7): 2954. (bBg), - p 2502, 1685, 1459, 1223. Microanalysis (С43Но5МО»2НСЙ) (calculation) C: 56.60 H: 9.98, M: 5.11; (result of "" analysis) C: 56.60, H: 9.85, M: 4.77. "H NMR (СО35О0) 5: 0.47-0.56 (t, 1Н), 0.78-0.89 (t, 8Н), 1.30-1.36 (t, ZM), " 1.61-1.79 (t, 5H), 2.58 (v, 2H), 2.99-3.10 (t, 4H).

EXAMPLE 60: (1-aminomethyl-4-ethyl-cyclohexyl)-acetic acid hydrochloride g. ay -0..50 С Bo «С -0, F DV, F: m, Se i F t (yozi uEOV) boss zheoah gi i b (503 z ; Example 60

HF) Stage i: synthesis of 2-cyano-(4-ethyl-cyclohexylidene)-acetic acid ethyl ether (boa):

HF 4-ethylcyclohexanone (13.0g, 103.0mmol) was dissolved in toluene (150ml) and treated with ammonium acetate (0.79g, 10.3mmol), glacial acetic acid (1.2ml) and ethyl cyanoacetate (11.65g, 103.0mmol). The reaction mixture was refluxed for 56 hours with a Dean-Stark trap, then cooled to room temperature of 60 °C and washed with NaO (2 x 100 ml). The aqueous layer was additionally washed with toluene (2 x 15 Oml). The organic layers were combined, dried over Ma2O, and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 5:1 hexane/ethyl acetate to give 19.81 g (8795) of the desired product as a clear yellow oil (boa). and Mass spectrometry: 222.1 (M for Со43Н4е9МиО2); butter; TLC: Zi", KYUO.93 (1:11 hexane/EOdAs);

IR spectroscopy (KVh, cm 7): 2931, 2225, 1728, 1602, 1223. "H NMR (SOSIv) 8: 0.82 (5 NM, 9U-7.4Hz), 1.11-1.38

(t, 7H), 1.39-1.45 (t, 1H), 1.90-2.09 (t, ЗН), 2.20-2.28 (t, 1H), 2.91-2.98 (t, 1H), 3.75-3.79 (t, 1H) , 4.15-4.20 (t, 2H).

Stages: synthesis of cis-1-cyanomethyl-4-ethyl-cyclohexanecarbonitrile (6065): 2-Cyano-(4-ethyl-cyclohexylidene)-acetic acid ethyl ether (bba, 16.57g, 74.86bmMol) was dissolved in EUN (100ml) and added to the suspension of Masm (3.67 g, 74.86 bmol) in EUN/H-O (30 Oml/1 bml). The reaction mixture was refluxed overnight, then cooled to room temperature and filtered to remove the precipitated salt (4.58 g). The filtrate was concentrated under vacuum to give a clear, very viscous, yellow oil. The residue was subjected to flash chromatography on silica gel, eluting with 16:11 7/0 hexane/E(OAc) to give 11.82 g (77790) (a mixture consisting of 8195 cis and 1995 trans isomers) of product as a yellow oil (bos) .

Mass spectrometry: Myai1 ion was not observed (C 44H36Mo); butter; TLC: Zi", KO.55 (21 hexane/EUAs);

Microanalysis (C44Ni6Mo) (calculation) C: 74.96 H: 9.15, M: 15.89; analysis result) C: 74.84, H: 8.97, M: 15.74. IR spectroscopy (KVh, cm"): 2934, 2240, 1453. "H NMR (SOZO0) 5 0.90 (Yii, ZM, 9U-7.6Hz), 1.18-1.47 (t, 7H), 75. 1.83-1.87 ( t, 2H), 2.07-2.10 (t, 2H), 2.85 (c, 2H).

Step 1: Synthesis of cis-(1-cyano-4-ethyl-cyclohexyl)-acetic acid ethyl ether: cis-1-Cyanomethyl-4-ethyl-cyclohexanecarbonitrile (606, 6.16 g, 34.95 mmol) was dissolved in EN (92 ml) and toluene (92 ml), cooled to 09C and saturated with gaseous NSI. The solution was tightly closed and left to stir overnight at room temperature. It was then concentrated under vacuum to give a yellowish-white solid. The residue was triturated with ethyl ether (200ml) and dried under vacuum, then treated with HO (900ml) and 1M HCl (4ml) was added. The reaction mixture was stirred overnight at room temperature and after 18 hours the formation of yellow oil droplets was observed in the solution. The compound was extracted

EUAs (Zh 100 ml); the organic layers were combined, washed with saline, dried over NaCl, and concentrated. The residue was subjected to flash chromatography with 16:11 hexane/(EMOAc) to obtain 4.40 g (5690) of the required product (bos).

Mass spectrometry: 224.1 (MAT for С 43Н24МО»),. butter; TSHKH: i", KYU.38 (SNSI"); Microanalysis (С413Н24МО») (calculation) C: 69.92 H: 9.48, M: 6.27; analysis result) C: 69.97, H: 9.49, M: 6.17. IR spectroscopy (KVh, cm): 2930, 2236, 1736, 1187. "H NMR (СО5О0) 5: 0.87-0.90 (t, ZM), 1.18-1.46 (t, 10M), 1.77-1.80 (t, 2Н ), 2.05–2.09 (t, 2H), 2.59 (5, 2H), 4.13–4.15 (t, 2H). -Z-one (608): - cis-(1-Cyano-4-ethyl-cyclohexyl)-acetic acid ethyl ether (603, 2.7 g, 12.1 mmol) was dissolved in Meon (250 ml) and processed at 1095 Rp/290Ra/С (0.5 g), after which it was shaken in an atmosphere of H 5 (5 Org) for 3 hours. Then the reaction mixture was filtered, concentrated under vacuum and chromatographed on silica gel, eluting with 395

Meon/snesi" to give 1.13g (52905) of the desired product as a white solid (604).

Mass spectrometry: 181.0 (M-1 for С 44Н49М4104); Tdl 131-1339S; TSHKH: 5i", KO.22 (496 MEeON/СНоСИ"); uh-

Microanalysis (C44Ni8M10.4) (calculation) C: 72.28 H: 10.08, M: 7.66; (analysis result) C: 72.66, H: 10.45, M: 7.26. IR spectroscopy (KVg, cm 7): 3197, 2918, 1680. "H NMR (SOCI3) 5 0.83-0.97 (t, 5M), 1.06-1.23 (t, ZM), 1.31-1.39 (t, 2H), 1.63-1.67 (t, 4H), 2.09-2.11 (t, 2H), 3.15-3.17 (t, 2H), 5.73 (rg, 1H).

Step M: synthesis of the compound of example 60: 8-ethyl-2-azo-spiroI(4,5|decan-3Z-one (604, 3.8g, 21.1mmol) was treated with concentrated HCl (141ml) and heated at 110927 for 24 hours The reaction mixture was then concentrated and recrystallized from hot isopropanol (2 Oml) and acetone to obtain 3.3 g, (16.6 bmol, 79905) of product. . CARRIERS) (calculation) C: 56.04 H: 9.41, M: 5.94; (analysis result) C: 56.06, H: 9.46, M: 5.88. IR spectroscopy (KVG, cm"): 2916 (bg), 1698, 1526, 1281. "H NMR (SOZOB) 5: 0.89 (i, ZM, 9U-7.3Hz), 1.02-1.40 (t, 8H), 1.68 (i, 4H, U-16.1Hz), 2.38 (5, 2H ), 3.13 (c, 2H). Example 61: (1-aminomethyl-4-propyl-cyclohexyl)-acetic acid hydrochloride (9)

Ma bank Y boze - t go F vK( v, F "Vu v! I (U. Y. F o (tu) 161) bis) chvi 0 Prykavd 61 6o Stage i: synthesis of 2-cyano-(4-propyl- cyclohexylidene)-acetic acid ethyl ether (614): 4-n-propylcyclohexanone (14.0 g, 99.4 mmol) was dissolved in toluene (145 mL) and treated with ammonium acetate (0.77 g, 9.98 mmol). glacial acetic acid (1.1 ml) and ethyl cyanoacetate (11.3 g, 99.8 mmol). The reaction mixture was refluxed overnight with a Dean-Stark trap, then cooled to room temperature and washed with HO (2 x 200 mL). The aqueous layer was additionally washed with toluene (Zh 200 ml). The organic layers were combined, dried over MgO, and concentrated under vacuum. The residue was chromatographed on silica gel,

eluting with 8:1 hexane/ethyl acetate to give 21.58 g (92965) of the desired product as a clear yellow oil (614).

Mass spectrometry: 236.1 (M-1 for С44Н24МО»); butter; TLC: Z", KO.57 (8:11 hexane/!E(OAc); Microanalysis (C14H24MO") (calculation) C: 71.46 H: 8.99, M: 5.95; (analysis result) C: 71.38, H: 8.92 , M: 6.10.

IR spectroscopy (KVh, cm"): 2929, 2225, 1728, 1603, 1227. "H NMR (SOCI3) 5: 0.83 (, ЗН, 9-7.3Hz), 1.07-1.30 (t,

OH), 1.51-1.56 (t, 1H), 1.91-2.00 (t, 2H), 2.04-2.12 (t, 1H), 2.23-2.30 (t, 1H), 2.95-3.01 (t, 1H), 3.77- 3.83 (t, 1H), 4.20 (d, 2H, 9-7.1Hz).

Stages: synthesis of cis-i-cyanomethyl-4-progyl-cyclohexanecarbonitrile (616): 70 2-Cyano-(4-n-propyl-cyclohexylidene)-acetic acid ethyl ether (6b1a, 19.46 g, 82.70 mmol) was dissolved in

EUN (100ml) and added to a suspension of Masm (4.053g, 82.7b0mmol) in EUN/NoO (340ml/20ml). The reaction mixture was refluxed overnight, then cooled to room temperature and filtered to remove precipitated salt. The filtrate was concentrated under vacuum to give a clear, very viscous, yellow oil. The oil was redissolved in E(OAc) and washed with saline solution 75 (2 x 150 ml), dried over Ma»5O, and concentrated. The residue was subjected to flash chromatography on silica gel, eluting with 19:1 hexane/(E(Ac) to obtain 4.69 g of 616 (7496 ).

Mass spectrometry: Myai1 ion was not observed (C 42Nu8Mo); butter; TLC: z", KO.38 (3:11 hexane/EUAs);

Microanalysis (C42NivMo) (calculation) C: 75.74 H: 9.53, M: 14.72; analysis result) C: 76.05, H: 9.58, M: 14.90, IR spectroscopy (KVh, cm"): 2931, 2239, 1453, 758. "H NMR (SOSI") 5 0.86 (I, ZM, 9-7.1 GHz), 1.18-1.34. (t, 7H), 1.42-1.61 (t, 2H), 1.81-1.83 (t, 2H), 2.06-2.09 (t, 2H), 2.65 (v, 2H).

Step 1: synthesis of cis-(1-cyano-4-propyl-cyclohexyl)-acetic acid ethyl ether (61c): cis-1-Cyanomethyl-4-n-propyl-dcyclohexanecarbonitrile (616, 3.87 g, 20.34 mmol) was dissolved in EN (5Oml) and toluene (bbml), cooled to 09С and saturated with gaseous NCI for 20 minutes. The solution was tightly closed and left to stir overnight at room temperature. Then it was concentrated under vacuum with 29 3 to obtain a yellowish-white solid. The residue was triturated with ethyl ether (200 ml) and dried under a vacuum, then dissolved in HO (8 ml) and 1 M HCl (4 ml) was added. The reaction mixture became clear after 4 hours of stirring, after which it was continued to stir overnight at room temperature. After 18 hours, the formation of drops of yellow oil was observed in the solution. The compound was extracted with EtOAc (4 x 20 Oml); the organic layers were combined, washed with saline solution (2 x 200 ml), dried over NaCl and concentrated. with

The residue was subjected to flash chromatography with 19:1 hexane/(E(OAc) to obtain 3.27 g of product (61 z, 6890).

Mass spectrometry: 238.1 (М--1 for С43Н2414МО»); butter; TSH: Zi, K.38 (СНоСи»); Microanalysis (С413Н24МО») oyu (calculation) С: 70.85 Н: 9.77, М: 5.90; analysis result) C: 70.65, H: 9.72, M: 5.84. IR-spectroscopy (KVh, cm: 2929, 2236, 1736, 1185. "H NMR (SOCIz) 5: 0.85 (0 ZM, 9U-7.1 GHz), 1.19-1.55 (t, 1OH), 1.71-1.74 (t, 2n),

Sv 2.08-2.10 (t, 2H), 2.59 (v, 2H), 4.16 (ad, 2H, U-7.1Hz). M

Step 1: synthesis of cis-8-propyl-2-azo-spiroI(4,5|decan-3-one (614): cis-(1-Cyano-4-propyl-cyclohexyl)-acetic acid ethyl ether (613, 8.27g, 34.8MmMol) was dissolved in Meon (9FOml) and treated with triethylamine and 1095 RI/2906R a/s (0.5g), after which it was shaken in an atmosphere of H 5 (5 Org) for 55 hours. Then the reaction mixture was filtered, concentrated under vacuum. The residue was chromatographed on "silica gel, eluting with 5:1 hexane/E(OAc) to give 6.41 g (614, 9495) of the required product. ssh s Mass spectrometry: 196.1 (Mya-1 for C 42H24MO); oil; TLC: Z", Cab. 38 (hexane/E(OAc); Microanalysis. (С12Н24МО) (calculation) С: 73.80 НН: 10.84, М: 7.17; (analysis result) С: 73.86, Н: 10.76, М: 7.11. "» IR- spectroscopy (KVh, cm 7): 3192, 2924, 1704, 1678. "H NMR (SOSIv) 5: 0.83-1.17 (t, 5H), 1.18-1.39 (t, 7H), 1.61-1.65 (t, 2H) , 1.71-1.74 (t, 2H), 2.11 (5, 2H), 3.16 (c, 2H), 5.85 (bBg, 1H).

Stage M: synthesis of the compound of example 61: (1-aminomethyl-4-propyl-cyclohexyl)-acetic acid hydrochloride: - and 8-propyl-2-azo-spiro|(4,5|decan-3-one (614, 5.8 g, 29.75 mmol) was treated with concentrated NOSI (15 Oml) and heated at 1159C7 overnight. The reaction mixture was allowed to cool to room temperature, observing the formation of a precipitate. The precipitate was filtered to give 3.47g of a white solid, and the filtrate was cooled and filtered to give 1 in the amount of 6.24 g (9995) of the required product. -1 50 Mass spectrometry: 214.1 (Me1 for С42Н23МО»); Tdl 142-14492С; Microanalysis (С42Н2з3МО».NeСЙ.0.86Н20) (calculation) С: 58.91 Н: 9, 83, M: 5.72; (analysis result) C: 59.27, H: 9.60, M: 5.71. "H NMR (СО3О0) 5: iz 0.86-0.90 (t, ZM), 0.97-1.41 (t, 1OM), 1.61 -1.75 (t, 4H), 2.37 (v, 2H), 3.13 (v, 2H), IR spectroscopy (KVg, cm 7: 2919, 1702, 1525, 1461,1188. rya EXAMPLE 62: ((ZK,55 )-3,5-dimethyl-1-propylaminomethyl-cyclohexyl)-acetic acid hydrochloride

(ZK,55)-1-aminomethyl-3,5-dimethyl-cyclohexyl)-acetic acid hydrochloride (59a, 0.5 g, 2.12 mmol) -BO0-

dissolved in ethanol (45 ml) and treated with 1 M Mahon (1.8 ml). Then propionic aldehyde (0.5 ml, Zeq.) was added and the reaction was treated with Ri. (0.2g). Then the mixture was shaken in an atmosphere of No (5 Org) for an hour. The reaction mixture was filtered, 1M HCl in ether (ml) was added and concentrated under vacuum. The residue was dissolved in hot

IVOpropanol (100 ml) and filtered. The filtrate was concentrated and recrystallized from hot isopropanol (dml), ESO (225 mL), and hexane (15 mL) to give 20 mg (0.83 mmol, 3995) of product.

Mass spectrometry: 242.1 (Mat for С 44Н27 МО»); IR spectroscopy (KVh, cm"): 2952 (horn), 1686, 1457, 1218.

Microanalysis (С44Н27МО». NSI.0.24Н250) (calculation) С: 59.60 Н: 10.17, М: 4.96; (analysis result) C: 59.68,

H: 10.09, M: 4.64.!H NMR (СО83О0) δ: 0.48-0.57 (t, 1H), 0.78-1.05 (t, 11M), 1.61-1.78 (t, 7H), 2.60 (zv, 2H), 70 2.93-3.00 (t, 4H).

EXAMPLE 63: (1K,3K)-1-(benzylamino-methyl)-3-methyl-cyclohexyl)-acetic acid hydrochloride ha: a aa o

J

(1K,3K)-1-Aminomethyl-3-methyl-cyclohexyl)-acetic acid hydrochloride (Example 1, 3.0g, 13.5mmol) was dissolved in ethanol (80ml) and treated with 1M Mahon (14ml, 1eq.). Then benzaldehyde (4.Bml) and 1095 were added

Ra/s (1.0 g) and the mixture was shaken in a Neo atmosphere (5 Orzi) for 2.75 hours. The reaction mixture was filtered, 1M was added

NS in ether (200 ml) and concentrated under vacuum. The residue was dissolved in hot isopropanol (1O0Oml), filtered and concentrated under vacuum. The residue was dissolved in the minimum required amount of hot isopropanol and recrystallized from ether. The solid phase was filtered off and the filtrate was cooled overnight to obtain a second batch of crystals. The solid phase was combined to obtain 1.35 g (36905) of the required product.

Mass spectrometry: 276.1 (M-1 for С47Но5МО»); High resolution mass spectrometry: (calculation) c 276.1963 (analysis result) 276.1962 (Ma-1 for С 17Но5МО»); Tpl. 157-1582C; IR-spectroscopy (KVg, cm"): 2932... ich- (Bg), 1691, 1450, 1201. Microanalysis (С.47Но5МО2НСЙИ 0.24Н20) (calculation) С: 64.58 Н: 8.44, М: 4.43; (result analysis) C: 64.57, H: 8.44, M: 4.28. "H NMR (СО5О0) 5 0.77-1.69 (t, 12Н), 2.42 (in, 2Н), 3.21 (in, 2Н), 4.25 (in, 2Н ), 7.43-7.52 (t, 5H). at

EXAMPLE 64: D1K,3K)-1-(benzyl-methyl-amino)-methyl|-3-methyl-cyclohexyl)-acetic acid hydrochloride cha

And 1 Yes, ZOZ Z

Iz» TU: I used to eat. IR,ZK)-1-(Benzylamino-methyl)-3-methyl-cyclohexyl|-acetic acid hydrochloride (Example 63, 1.02g, (9) 3.27mmol) was dissolved in ethanol (40ml) and treated with 1M Mahon (3.3ml , Ineq.). Then formaldehyde sl (2.Bml) and Pb (0.1g) were added and the mixture was shaken in an atmosphere of No (5 Org) for 8 hours. The reaction mixture was filtered, 1 M NOI in ether (1 Oml) was added and concentrated under vacuum. The residue was dissolved in hot isopropanol (100 ml), and 50 ml was filtered and concentrated under vacuum. The residue was dissolved in the minimum required amount of hot isopropanol and recrystallized from ether and hexane. The solid phase was collected to obtain 0.704 g (2.1 b6 mmol, 6690) of the required product.

Mass spectrometry: 290.1 (С 8Н27МО»); High resolution mass spectrometry: 290.2128 (С 418Н27МО»); Tpdl 5 204-2052C; IR spectroscopy (KVh, cm"): 2926 (bg), 1720, 1457, 1387, 1203.1Н NMR (СО3О0) 5: 0.82-0.98 (t, 5Н), 1.24-1.91 (t, 7Н), 2.38-2.58 (t, 2H), 2.91 (y, ЗН, 9-11.2Hz), 3.43-3.54 (t, 2H), 4.33-4.49 (t, 2H), 7.50-7.56 (t, 5H).

F) EXAMPLE 65: (1K,3K)-3-methyl-1-methylaminomethyl-cyclohexyl)-acetic acid hydrochloride ime) 60 b5

; Vo. bbov

DI1K,ZK)-1-(Benzyl-methyl-amino)-methyl|-3-methyl-cyclohexyl)-acetic acid hydrochloride (Example 64, 0.60 g, 1.84 mmol) was dissolved in ethanol (500 ml). 1095 Ra/sС (0.1 g) was added and the mixture was shaken in an atmosphere of No" (5 Orzi) for 7 minutes. The reaction mixture was filtered, 1M HCl in ether (5 ml) was added and concentrated under vacuum. t5 The residue was dissolved in hot isopropanol (10 Oml), filtered and concentrated under vacuum. The residue was dissolved in the minimum required amount of hot isopropanol and recrystallized from ether and hexane.

The crystals represented 0.15 g (3595) of the required product.

Mass spectrometry: 200.1 (M-1 for С44Н54МО»); High-resolution mass spectrometry: (calculation) 200.1650 (analysis result) 200.1646 (Ma-1 for С44Н24МО»); Tpl. 160-1612C; IR spectroscopy (KVh, cm"): 2925 (B), 1719, 1457. Microanalysis (С44Н24МО». NSI.0О.40Н20О) (calculation) С: 54.38 Н: 9.46, М: 5.77; (analysis result) С: 54.27, H: 9.36, M: 5.65. "H NMR (CO35O0) 5: 0.83-0.97 (t, 5H), 1.20-1.28 (t, 1H), 1.42-1.74 (t, 6H), 2.38 (8, 2M ), 2.73 (in, ZM), 3.23 (in, 2H).

EXAMPLE 66: Summary of Ha

Using an ex mimo model of a freshly excised rat retina, the mechanisms of maintaining the level of glutamate in brain tissues within normal limits were investigated. Anaplerotic glutamate synthesis may be an important process for replenishing glutamate oxidized in glia as a result of neurotransmission. Carboxylation of pyruvate and transamination of branched-chain amino acids were identified as level control points in these new metabolic pathways. In order to check the relationship between glutamate synthesis and carboxylase activity, Ge studied the synthesis of "C-glutamate - "C-glutamine from НАСО3С as a function of the pyruvate content in the medium. M

Increasing the concentration of pyruvate from 0.2 to 5 mM increases the synthesis of "C-amino acids" by 66 -/-1595. The specific radioactivity of glutamine relative to H'CO3 after 20 minutes of incubation showed that "3095 glutamine in the retina is produced from bicarbonate. To check the dependence of glutamate synthesis on the presence of branched-chain amino acids (BCAA) as nitrogen sources, the effect of inhibiting neuronal aminotransferases was studied.

Of branched-chain amino acid-dependent (BCATs). Gabapentin (GBP) (1mM), a selective inhibitor -

BSATs in neurons, inhibited the synthesis of "C-glutamate" C-glutamine from НЕСОзЗ at 3195 without delaying the inclusion

H"CO" to lactate and intermediates of the citric acid cycle. Inhibition of glutamate de pomo synthesis can be reversed by the addition of 0.6 mM BCAA. Existing data show that pyruvate carboxylase and branched-chain amino acid-dependent aminotransferase both control glutamate de pomo synthesis. pomo y from the retina and that the synthesis of glutamate de pomo is quantitatively important for maintaining the level of glutamate in the retina. c Methods: c» Experimental animals

Zrgadze YuOamieu rats (200-400 g) were used for the experiments. Rats were kept under a 12-hour light cycle, fed and fed ai Iridyt. After anesthetizing the rats with nembutal - 15 (intraperitoneally), the eyes were pulled out and the retina was excised in a buffer cooled on ice.

Incorporation of CO» 1 Freshly obtained preparations of stat-retina were preincubated at 372C for 3 minutes in buffer A (pH7.4) containing 118 mM Masi, 4.7 mM KSI, 2.5 mM Sasi», 1.2 mM KNoRO,, 1.17 mM M95O,, 20 MM NEREZ5, 5 MM glucose, 0.05 MM 50. MNASI and 25 MM Ma""Co"5. Pyruvate (either 0.2 or 5 mM) was also included in the buffer. i ml of buffer, as well as 7 gas phase in a 20 ml vial was balanced with 9595 05, 595 So. Incubation was initiated by the addition of 10 µC/ml of HCO. The vessels were immediately sealed from the atmosphere. The longest incubation time was 20 minutes, although in some previous studies the incubation time varied from 10 to 60 minutes. The reaction was stopped by removing the semi-retina from the buffer. and placing it in perchloric acid 295. The buffer was separately acidified with perchloric acid (final concentration 295) and unreacted "7CO" was allowed to diffuse from the acidified sample.

F! The total amount of the product (non-volatile "7C-metabolites) was determined by measuring radioactivity in aliquots of medium and tissue samples. Metabolites in the extracts were isolated using chromatography on Oomzheh-1 acetate, as described in: MUyShiatwop, 9. K., Apia Sogseu, V (1969) "Meiyodvs ip Eplitoiodu", moi.13, ey.

I omzhepviviip, y). M. (Asadetis Rgezv) years 434-513), and carried out quantitative determination on a scintillation counter. In most cases, data on individual 14b-metabolites are shown as the sum of radioactivity in the medium and tissue extracts. Complete quantitative characterization of "C-metabolites in both the retina and the medium is demonstrated in Tables | and II.

The results and discussion section do not show the data collected during the evaluation of the effect of vepyruvate on the inclusion of HCO" in the retina. Fig. 2 shows only the effect of pyruvate on the amount of glutamatyglutamine and the amount of pyruvate lactate. In Table | the values for all metabolites including the HCO" label and their distribution are shown.

Similarly, additional data not shown in the results and discussion section relate to the evaluation of the effects of gabapentin. Table II is more detailed data shown in Fig.4 and includes values for all metabolites labeled H'""CoO" and their distribution. Nina Nina (0.2 Pyuvat) and 000 Oppovosostovostovogooe 01797075 Was 102g (277 tat ooo ovo 005 o0Bo: 006 1000 0705 3716 0206 1 en ovo ovo otog oatv:ooyu 0 1ltt: ost ee ovomoovi levi ooevtoya: ooo ov; ooo! 109; 0105 vza: 03

APPLE 0100800 ozvgooov am: ooo: ooo ovo; 0006 1514: 0109 5902: 0122 te ovivioomioov; ooo: oyu ovivgoovo 0 tovv: osv sch 2 ee oemioozv zo orvy: ooo? this ooo 1514: 0109 vv: osv o

ЗГБЛЕВСАА 800 Авга Аю ото Тов: от осв: 0006 12205 0116 559: ОЗ te ovovioooovooyur ooo ovo: oleviosiv 0 to ootv 77 ma ovvuovotobvuoootoolorh osteo vmeh o0to oh oltv 530 M sch

The chromatographic technique used in this example separates glutamine, glutamate, aspartate, and lactate. The intermediates of the citric acid cycle remain on the Juoumech column and are estimated as the difference between the total number of pulses in the sample and the number of pulses in the eluted material. The proof of the applicability of such a technique was given earlier. Before subjecting the sample to chromatographic separation, "C-pyruvate in sample M is stoichiometrically converted into lactate by treating the sample with an excess of MAOH and lactate dehydrogenase. Therefore, M the only lactate peak on the chromatogram contains all "C" that originally belonged to both lactate and pyruvate. To determine the specific activity of glutamine and glutamate in retinal samples, the mass amount of glutamate was measured fluorimetrically, using a standard enzymatic technique: Raiei!i, M. 5. (1989) ip Megpoteipoaev:

Sagropudgaee apa Epegdu Meiaroiivt, mo! II, Edv. Votsshop, A.A. apa WaKeg b. O. (Te Nytapa Rgezv, Ips.) « pp. 309-340. The mass amount of glutamine was determined after chromatographic separation from glutamate with subsequent, previously described luminometric determination. ATP and creatine phosphate were measured fluorimetrically using an enzymatic method. Retinal protein was determined using the OS protein determination method (Vio-Kai, Kisptopa, SA, OA).

Each stat retina contained approximately 0.4 mg of protein.

Pyruvate carboxylase method - I Activity of pyruvate carboxylase was determined on fresh samples of whole brain and excised retina. The method described by Raiei!, M. 5. (1989) ip Meiigoteipodz: Sagropuadgaie apa Epegdu Meijaroiizt, mo! II, Edv. Votsshuop, A.A. i-y apa Wakeg b. 0. (Tne Nytapa Rgezz, Ips.) pp. 309-340), was used to measure CO inclusion under optimal conditions in tissues subjected to ultrasonic disintegration.

Protein blotting (Uuviegp Wioi) and electrophoresis in 50O5-PAGE was performed (as described in Raiei!, M. 5. (1989) ip Mapgoteipodz: Sagropuagaye apa

Kz Epegdu Megaroiivt, mo! II, eavs. Votsshiop, A.A. apa Wakeg village 0. (Te Nytapa Rgevzv, Ips.) 309-340), using 1095 gels. For immunoblotting, proteins were transferred to Ittorbiop R. membranes. The membranes were blocked with 595 BSA and incubated with immunoaffinity-purified rabbit-anti-rat antibodies to BSATs peptides (1:1000 dilution). Immunoreactive protein bands were visualized using the ECI system. according to the manufacturer's instructions (Ategepat, Agiipdyup Neiidniv, I, OBA). iF) Calculations and statistics. The data are presented in the text and in the figures as values of drt/mg in a specific metabolite divided by the specific activity of HSO»z in the environment. Therefore, all data are presented as nMole H"CO3/mg protein for any given metabolite.

Results are presented as mean 4 standard error of the mean. Statistical significance was assessed by a paired t-test and a p value of 0.05. the number of independent determinations (n) is indicated in the captions to figures and tables.

The level of pyruvate carboxylase is similar in the retina and whole brain. 65 Raye! showed that pyruvate carboxylase is the main CO-utilizing enzyme in the brain of adult rodents.

To determine whether this is also true for the retina, the activity of pyruvate carboxylase at 37 C in ultrasound-disintegrated tissues of the neocortex was compared with its activity in the retina. , found in ultrasonically disintegrated retinal tissues (3.44 0.4 nMol H'""CO" cond./min./mg), which suggests that pyruvate carboxylase is as active in the retina as it is in the whole brain.

Levels of CO incorporation and C-glutamate release are a function of retinal pyruvate levels.

In previous experiments, the retina was incubated with 0.2 mM pyruvate as described earlier for 10, 20, 40, and 60 minutes. Total "7CO" content and ATP and creatine phosphate levels were monitored. ATP and creatine phosphate levels remained constant as a function of time, demonstrating that oxidation and pH control were adequate. 70 Total CO incorporation (5.50-- 0.14nMol/mg protein) was maximal between 20 and 40 minutes, but reached 7695 from the maximum (4.2-- 0.1nMol/mg) as early as 10 minutes.As ATP (20- 0.2nMol/mg) and creatine phosphate (16-- 1.1nMol/mg) levels were high and did not change subsequently, this maximum shows that the level of incorporation of CO" was constant, but the constant decay of non-volatile ""C-products into CO" and HO gave a near-steady level of 7/5 glutamate/glutamine-bound radioactivity at 20- th minute

To investigate the effect of pyruvate carboxylation on glutamate synthesis, retinas were incubated with either 0.2 or 5 mM pyruvate in medium and analyzed for both intracellular and extracellular metabolites. The total incorporation of "7CO" in 20 minutes in the presence of 0.2mM pyruvate was 5.27 0.45nMol H""CoOz/mg, while the incorporation in the presence of 5MM pyruvate - 9.50-- 0.74nMol H'""COu/mg. Fig. 2 shows that an increase in unlabeled pyruvate from 0.2 to 5 mM increases the amount of "C-glutamate" C-glutamine (from 1.74 0.19 to 2.90--0.31nMol/mg, p«0.005). Fig. 2 also shows that incubation with a large amount of pyruvate increases the amount of "C-lactate" C-pyruvate.

Thus, in a steady state, increasing the concentration of pyruvate from 0.2 to 5 mM increases the incorporation of H CO5 into glutamate and glutamine by 6695, and into lactate and pyruvate by 11195. -enzyme and phosphoenolpyruvate-carboxykinase and primarily demonstrates decarboxylation activity in the citric acid cycle in intact nerve tissue. (8)

These data demonstrate that an increase in pyruvate carboxylase induces an increase in de pomo retinal glutamate synthesis. At the same time, a slightly greater increase in pyruvate turnover is found.

A significant part of the total synthesis of glutamate is due to carboxylation of pyruvate. The importance of carboxylation of pyruvate as a source of replenishment of glutamate released from the nerve endings of the retina during neuronal transmission was demonstrated by determining the specific activity of of glutamate in retinal tissues incubated with medium containing H'SbO3. A known part of the synthesis of glutamine in the retina is carried out from unlabeled glutamate, which is released by neurons and taken up by them

Muller. The other comes from glial ss-ketoglutarate, synthesized anaplerotically from pyruvate and CO." at

Therefore, the specific radioactivity of glutamine, relative to the specific radioactivity of НАСО3, gives the minimum value of that part of aglutamine formed during anaplerosis. The product of opyruvate carboxylase in glia is

I1,4- "CI-oxaloacetate. Both positions 1 and 4 are labeled because "C, initially incorporated into position 4 of oxaloacetate, is then randomized between positions 1 and 4 due to equilibration of oxaloacetate by symmetrical " fumarate. Labeled oxaloacetate condenses with pyruvate to form citrate, which then isomerizes to isocitrate. (1,4-7СІisocitrate is oxidized and decarboxylated to |5- "СІ-ketoglutarate with the help of не)с isocitrate dehydrogenase. Therefore, о,-ketoglutarate, synthesized anaplerotically, has approximately half the specific :з" radioactivity of the original substrate НЕСО, in depending on the degree of randomization of the label in oxaloacetate.

This is also true for glutamine synthesized from |5-7С1-y, -ketoglutarate.

The specific activity of glutamine was measured in extracts of retinal tissue incubated with 0.2 mM pyruvate -i and Hn'so. for 10, 20, 40 and 60 minutes. Data collected only for Pacific (non-environmental) glutamate.

The specific radioactivity of glutamate in the tissue was constant between the 10th and bbO-th minutes. After 20 minutes of incubation, the mass amount of glutamine in the tissue was 4.50--0.44 nMol/mg, and the specific radioactivity was 19704 115 1 art/nMol or 0.1581-0.009 art/nMol of the specific activity of bicarbonate. This suggests that approximately 32965 -1 50 of glutamine is produced anaplerotically and by pyruvate carboxylase.

The specific radioactivity of retinal glutamate (269-vart/mmol) was lower than that of glutamine and also

Iz was constant in the period from 10:00 to 6001 minutes. It was only 1495 of the specific activity of glutamine. This suggests that the metabolism of glutamate in neurons is faster than during anaplerotic synthesis. However, since glutamate turnover in neurons cannot replenish the carbon backbone of glutamate, the anaplerotic pathway lost during neurotransmission is of particular importance in maintaining glutamate levels in neurons.

Gee! The data presented unequivocally demonstrate that the anaplerotic pathway provides a significant portion (32965) of the glutamine required to replenish glutamate. ko Synthesis of retinal glutamate and glutamine partially depends on transamination of amino acids with a branched chain. 60 Recent studies of glutamate synthesis in astrocyte cultures suggest that the stage of conversion of A-ketoglutarate to glutamate may serve as a control stage in the anaplerotic synthesis of glutamate. Several groups have shown that the sso-amino group of glutamate cannot originate from ammonia and must therefore be delivered by transamination of A-ketoglutarate with another amino acid: Kapatogi, K., Kovzv, V.O., apa

Kopagai, MK. MU. (1998) U. Meigospet. 70, 1304-1315, I aettii, O. K. (1970) Maishge 227, 680-885, including our own b5 Nabeigto, A., OM, N., VakKKep, I.)., Zapde, YII. M., MUpiye, YII K., Nagaidze(y, O., Opzdaga, O., Avvievu, U.,

Zoppemaia, ). (1998) Yuem. Meygossy 20, 389-398. Amino acids with a branched chain are probably the source of -B4-

nitrogen, as they can effectively cross the blood-brain and blood-retinal barriers. Niizop from co. suggested that the nitrogen shuttle between neurons and glia, which includes branched-chain amino acids and two isozymes of BSAT: one from the cytosol of neurons (BSATc) and the other from glial mitochondria (BSATt),

May also provide nitrogen: Nyizop, 5. M., Wegkisp, O., Juom/p, R., Hy, V., Azsupeg, M., apa GaMopce, K. B. (1998) 9). Mayhospet, 71 863-874. According to this hypothetical shuttle, neuronal BSATs assist the glial conversion of A-ketoglutarate to glutamate with the participation of BSATt, providing BCAAs that are regenerated in neurons (see Fig. 1).

As a first step to study the role of BSAT isozymes in glutamate synthesis in the retina, immunoblotting with BSATc and BSATt-specific antibodies was used to determine whether BSAT isozymes are expressed in the rat retina. As shown in Figure 3, both BSATc and BSATt are expressed in the retina at a level comparable to that found in whole brain homogenates. Therefore, the freshly excised rat retina is a perfectly suitable intact nervous system for studying the concept of the nitrogen shuttle between neurons and glia.

The leucine analogue gabapentin (GBP) is a neuroactive drug that inhibits VSATs, but not VSATt: 5y, T.-27.,

Yitsppeu, E., Satrrbeii, b., Ohepaeg, Yu. Her. (1995) 9). Meigospet, 64, 2125-2131. GBP was confirmed to inhibit leucine synthesis in freshly excised rat retinas (data not shown). The effect of GBP on the synthesis of 14C-glutamate "C-glutamine from NS in the retina of the ex mimo rat was measured. As shown in Fig. 4, 1 mm of GBP suppresses the formation of "C-glutamate "C-glutamine by 71965 from the control value (2.26-- 0.05 vs. 3.18-- 0.12nMol/mg, p«e0.001). Addition of 200 MM each of leucine, isoleucine and valine transforms the inhibition by 8995 from the control (2.84-1.15nMol/mg, p«e0.01 against only GBP). No effect of GBP on ATP or creatine phosphate was detected, suggesting that GBP does not suppress bioenergetic processes in the retina. A small increase in the inclusion of C in lactate and intermediates of the citric acid cycle (from 1.934-0.06 to 2.120.13) due to the presence of 1 mM HBP is not significant. Label inclusion in all metabolites is shown in Table HER.

Further experiments were conducted to investigate the dose/response properties of GBP. Freshly excised retinas were incubated for 20 minutes in buffer A containing 0, 0.2, 1, or 5 mM GBP. As shown in Fig. 5, an increase in the concentration of HBpP by more than 1 mm does not lead to a noticeable increase in the inhibition of the synthesis of "C-glutamate" of C-glutamine from H''CO3. Also, GBP does not affect the formation of intermediates of the citric acid cycle, lactate and pyruvate (Fig. 5). This confirms the assumption that the site that GBP inhibits in the synthesis of glutamine is the BSAT-mediated conversion of o, -ketoglutarate to glutamate.

The described studies relate to the mechanisms of maintaining the level of glutamate in the central nervous system. Previous studies have shown that glutamate synthetase is necessary in the retina and hippocampal slices to maintain the level of neuronal glutamate: By, T.-7., | Ippeu, E. Satrei, 0., Ohepaeg, 0. I (1995) 3. Meshygospet, 64, 2125-2131.

Immunocytochemical measurements showed that 9095 or more retinal glutamate and whole brain glutamate are about

C5 Neuronal, and that inhibition of glutamine synthetase for 90 minutes depletes the neuronal store of glutamate to an insignificant level: ОЧЦегзеп, О.Р., 2япо, M., apa УУаИрегу, Г. (1992) Meiygovsi. 46, 519-534. This shows that glutamine synthetase is required to maintain neuronal glutamine levels. Although glutamate can be synthesized in neurons from A-ketoglutarate, removal of pyruvate carboxylase or another anaplerotic enzyme prevents the replenishment of A-ketoglutarate, and thus prevents glutamate synthesis within neurons, according to "

An exception to the path through glutaminase. - c In this example, the sources and control of glutamine synthesis were investigated by incubating excised retinas with NESO" and measuring the appearance and specific radioactivity of "C-glutamine and "C-glutamate. More "C-glutamine"" is synthesized in the presence of 5MM of pyruvate than in the presence of 0.2 mM pyruvate. This shows that pyruvate carboxylase activity affects the amount of glutamine synthesis. However, the lack of sensitivity of this type

The control is demonstrated by the observation that when pyruvate is increased from 0.2 to 5 mM, the increase in pyruvate carboxylase (80.396) does not cause an equivalent increase in "C-glutamine" C-glutamate (69.096). The dependence on pyruvate of the total inclusion of H "7СбО3 in retinal tissues is similar to that observed in astrocytes: Satrbegipo, MU. S, Vegkisp, YuO. A., Hipsp, S. 9., Khy, V., apa HaMotse, K. R. (1997) -I 20 3). Maphospet. 69, 2312-2325. However, in astrocytes that do not have pathways for regeneration of endogenous BCAAs used for transamination of A-ketoglutarate, pyruvate-induced increase in CO 5 utilization does not lead to increased levels of "C-glutamine" and "C-glutamate". Instead, C accumulates in intermediates of the citric acid cycle and in "recycling" pyruvate.

In the retinal studies described here, the steady-state specific radioactivity of glutamine was 59 0.158 that of bicarbonate. Since approximately half of the C included in oxaloacetate (F) was found in ss-ketoglutarate, the results show that 732965 glutamine is produced from H "7СО3. This is the first

This is direct evidence of the contribution of anaplerosis to the synthesis of glutamate in nervous tissue. Previous evidence was indirect and included isotopomer analysis of NMR spectra after infusion of "ZS-glucose (3-5, 11-13) into the intact brain. Estimation of the contribution of pyruvate carboxylation to glutamate synthesis using such NMR methods gave lower values in in the range from less than 195 (3) to 5-10905 (4.5) and up to 20-2595: Zpapk, K. R., Veppei, 0.5., Egeuiad, 5.O. . 329, 364-367, Sgiyep, U. |, Kae, S., Kaidaa, 0. K., apa Matsemuv, R. M. (1999) Viospit. Viorpuz. Asia 1450, 297-307, depending, obviously, from the initial assumptions in the mathematical model used.The presented results suggest that glial 65 carboxylation of pyruvate and the conversion of intermediates of the citric acid cycle to glutamate and glutamine are clearly important in a quantitative sense for retinal function and possibly for brain function in general.

The observation that GBP slows down the conversion of intermediates of the citric acid cycle into glutamine and glutamate clearly suggests that the neuronal synthesis of BCAA with the help of BSATc is necessary for the optimal level of amination of c; -xetoglutarate to glutamate. The corresponding scheme of involvement in this process is shown in Fig. 1.

The results showing the inhibition of the synthesis of "C-glutamate-"C-glutamine with НАСО3 gabapentin and the reversal of the inhibition of BCAA are fully consistent with the previously described shuttle. This hypothesis also makes it possible to explain the anti-epileptic effect of GBP: Tauiyuog, S.R. , See, M. 5., ZY, T. 27., Kosviv, U. O., MUemu, 0. E., Vhom/lp,

U. R., YuOsoieu, 0. 9., Vodep, bipoi, I. (1998) Erpierzu Kezv. 29, 233-249. Indeed, suppression of glutamate synthesis is a common effect of GBP and anti-epileptic carbonic anhydrase inhibitors: Nagep, 5. A., MUapeea, A., BU, MU. 5., 70 HaMotse, K. E., Gupsy, S. u. (1997) Yuem. MeshygozsiAV, 162-171. In addition, maple syrup disease is a hereditary disease caused by a mutation in the branched-chain ketoacid dehydrogenase gene, if left untreated, causes high levels of BCAA in the serum of patients and subsequent neurological complications: Sptsapa, 0.

And Apa pipp, M. E. (1995) ip Te Meiaroiis Vaziz oi Ippegpiyei Oivease, eaivs. Zsphimeg, S. K., Veatsaeyei, A..,

ZU, 5., apa Maye, 0. (MesOgam/-NIYII) 1239-1277, which may be associated with abnormal regulation 75 of glutamate synthesis. Finally, the participation of the nitrogen shuttle in the synthesis of glutamate should be studied further in the sense of the effectiveness of GBP in the treatment of neuropathic pain: ONCegvzep, O.R., 7yapo, M., apa MUUaIrego, R. (1992)

Metzgozsi 46, 519-534 and neurodegenerative diseases, Sptsapo, OO. I. apa pip, M. E. (1995) ip Te

Meiaroiis Vaziv oi Ippegiei Oizease, eiv. Zsphimeg, S. KK. Veatsdeib A, BU, 5., apa Maiye, 0. (MesOgamu-NIII) years 1239-1277, Koivzeyip, 9. Yu. apa Kipsi, K. MU., (1995) 3. Meigospet. 65, 643-651.

EXAMPLE 67

Preparation of the enzyme: frozen rat brains were thawed on ice and cut into small pieces. 5 ml of isotonic buffer (225 mm mannitol, 7 mm sucrose 5 mm MORZ (pH7.1), 1 mm EDTA, 1 mm DTT containing leupeptin, pepstatin and PMSF) was added to each brain. The samples were homogenized in a Potter homogenizer (V. Vhap

Vioiesp Ipiegpayopa!) at 500 rpm. (10 events) and at 800 rpm. (10 activities). The homogenate was centrifuged in sou

Centrifuge VesKtap 42-M1, rotor UA-20 at 19000o6./min. 1 hour. The supernatant was dialyzed against at least 3 changes of dialysis buffer (225mM mannitol, 75mM sucrose, ЖХММОРБЗ рН?7.1, 1MM EDTA, 1mM EITA and 1mM DTT) for 24 hours. The obtained enzyme was stored at -802C for further use.

VSAT procedure: the reaction was carried out in 1.bml Eppendorf tubes in a volume of 100 μl containing 50 OMM

Tris.HCI (pHV.3), 25 μl |"C)|i-leucine, 100mM 2-oxoglutarate, 15MkM pyridoxal phosphate, 1mM DTTt and enzyme. Solutions for the reaction mixture were made at a 10-fold concentration. After 1 hour of incubation at room temperature (2223), the reaction was stopped by adding 100 μl of 15 mM p-nitrophenylhydrazine in 2 M HCl. After a few minutes, ml of toluene-based scintillation liquid (4.5 g of PPO and 0.5 g of bis-M5B in T toluene) was added.

The test tubes were closed and thoroughly mixed on a Mogieh mixer. Then the test tubes were centrifuged at 13500°6/min. (centrifuge Errepdop 54152) for 10 minutes. Six hundred μl of the organic layer from each test tube was placed in

From the scintillation vials, 1 Oml of scintillation liquid was added for calculation. - « with Z s with jus that in 1 t v | lol

AND; y - 5 "with in 1 o in 1 yu in vv 28 181 -58v-

in 1 o vv cm o in 123- sch zo writes cha yu yuyu yu z shchi ni nich g c) "

Claims (14)

- - The formula of the invention and? 1. The compound of the IM formula Be. , -I t x son 1 1 - Hm I» - v. KE. B. de GF) K.-K. is hydrogen or C.-C.o-alkyl; 7 X is ME; K5 is hydrogen or C.-C.o-alkyl, Kv is C41-Cio-alkyl, benzyl, C-Ce-aryl-C.4-C-aralkyl, in which from 1 to 4 ring aryl atoms may be substituted a heteroatom selected from O, 5 or M, C4-C4o-Alkoxy, C3-C10-cycloalkyl, in which from 1 to 3 carbon atoms may be replaced by a heteroatom selected from 0, 5 or MEV2, where B2 is hydrogen or C-C0-alkyl, allyl, C4-C0-alkyl-C3-C0-cycloalkyl, in which from 1 to 3 cycloalkyl ring atoms can be replaced by a heteroatom selected from O, 5 or ME?, where BK? has the above value, trisubstituted b5 halogen-C-Cio-alkyl, and the specified alkyl, alkyl, allyl groups can be substituted preferably by 1-3 groups selected from the group that includes MK 125, where K7 and B? mean hydrogen or C.4-C.o-alkyl, unsubstituted or substituted phenyl, thio-Ci-Cv-alkyl, Ci--Ci-alkyl, hydroxy, carboxy, C-Ci-alkylcarbonyl, halogen, nitrile, C3-Ci0-cycloalkyl, and 5- or b-lene a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, which in turn may be substituted C.-Cv-alkyl or unsubstituted or substituted halogen (CH0).phenyl, where n means 1, 2 or 3, oxygen and sulfur; wherein said cycloalkyl groups may be substituted with a hydroxy group or a keto group, and said aryl and benzyl groups may be substituted with 1, 2 or C groups selected from the list including C.4-Cio-alkyl, optionally substituted as indicated above, C.4-Cio-alkyl, optionally substituted as indicated above, thio group, thio-C4-Cio-alkyl, hydroxy, carbonyl, group of the formula -MA "В?, Т(СНо)тОВ" or Т(СНо)тСО»В, where 70 т means from 1 to 6, T means O, 5, ME? WHAT" "MA"? or SVB", O means O, 5, MER, WHAT? or MAV, where B and VE? are defined as above and VU means unsubstituted or substituted as above, C.-Co-alkyl; and if K./-Ku is each hydrogen, then Ke is not methyl; or a pharmaceutically acceptable salt, ester or amide thereof. 2. The compound according to claim 1, where K» and K. are hydrogen, and K. and Kz are C4--C4o-alkyl; K» and Ku are hydrogen, and K. and Kz are methyl; K.-Ka 79 is hydrogen; Ku is C4-C.o-alkyl, and Co is K. is hydrogen; Ku is methyl and Co-Ku is hydrogen; K" is hydrogen; X is MK; X is 0; Co is C4-C4o-alkyl; Ke is benzyl; Co is acetyl; Co is phenyl-C4-C10-alkyl; Ke is C3-C40-cycloalkyl in which at least one cycloalkyl ring atom can be replaced by a heteroatom selected from 0, 5 or ME, where B? has the above value; K 5 is trifluoro-C.4-Cio-alkyl; Kv is C4-C4o-alkyl-C3-C-o-cycloalkyl, in which at least one ring cycloalkyl atom can be replaced by a heteroatom selected from 0, 5 or ME, where 2 has the above value; K 5 is a C 1 -C 10 -alkoxy group and Co is allyl, and these groups may be substituted as indicated above. Z. The compound according to claim 1, where K» and K. are hydrogen, and K. and Kz are methyl; K.-Ku is hydrogen; Ku. is methyl, and Co-K. is hydrogen; K5 is hydrogen; X is MK; Kw is C41-Cio-alkyl; Ke is benzyl; Ke is phenyl-C4-Ci0-alkyl; Ke is a C3-C100-cycloalkyl in which at least one ring atom of the cycloalkyl can be replaced by a heteroatom selected from 0, 5 or сч MAK, where B? has the above value; Kv is trifluoro-C,4-Cio-alkyl; Ke is C41-C40-alkyl-C3-C400-cycloalkyl, in which (8) at least one ring cycloalkyl atom can be replaced by a heteroatom selected from 0, 5 or ME, where B? has the above value; Kv is C41-C10-Alkoxy and Co is allyl, wherein said groups may be substituted as indicated above. with 4. The compound according to claim 1, where K» and K. are hydrogen, and K. and Kz are methyl; K.-Ku. is hydrogen. 5. The compound according to claim 1, selected from the group including: - 1о5,3рф,5р8. -(3,5-dimethyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; yu 1T1o,38,5rD. "(1-ethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 15.38 58 -K1-benzylaminomethyl)-3,5-dimethylcyclohexyl|-acetic acid hydrochloride; at 155.38 58. 1-dimethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; - 155,938.58. "(1-butylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 155.98. ,58. -1-(benzylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 1To, 38, 5 years. -(3,5-dimethyl-1-methylaminomethylcyclohexyl)-acetic acid hydrochloride; « 15.38 58 -1-(isobutylaminomethyl)-3,5-dimethylcyclohexyl/|-acetic acid hydrochloride; From t0 15.38 5 years. -3,5-dimethyl-1-(phenethylaminomethyl)-cyclohexyl)|-acetic acid hydrochloride; with 15,38 ,5r8. -443,5-dimethyl-1-((3-phenylpropylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(cyclobutylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 155.38 58 -I1-(isopropylaminomethyl)-3,5-dimethylcyclohexyl|)|-acetic acid hydrochloride; 11-(2-methylbutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; - 11-(4,4,4-trifluorobutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-ethylaminomethylcyclohexyl)-acetic acid hydrochloride; 1 11-Kcyclopropylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; c (1-(isobutylaminomethyl|-cyclohexyl|-acetic acid hydrochloride; (1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; - P1-(isopropylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; Kz (1-cyclohexylaminomethylcyclohexyl|-acetic acid hydrochloride; P1-(benzylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; (1K,3K)-3-methyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(cyclopentylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11- (cyclohexylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (F) P1-"tert-butoxycarbonylaminomethyl)-cyclohexyl|-acetic acid; GI (3K,55)-1-cyclobutylaminomethyl)-3,5-dimethylcyclohexyl|-acetic acid hydrochloride; u3K,55)-3,5-dimethyl-1-((2-methylbutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; in T(3K,55)-1-(2,2-dimethoxyethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; T(3K,55)-1-(cyclopentylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; T(3K,55)-1-Kcyclohexylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-cyclohexylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (1-butylaminomethylcyclohexyl)-acetic acid hydrochloride; 65 11-(2,2-dimethoxyethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-methylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(benzylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; P1-Cphenethylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; 11-CZ-phenylpropylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-ethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (ZK,55)-3,5-dimethyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; I1Kk,ZK)-1-(benzylaminomethyl)-3-methylcyclohexyl|-acetic acid hydrochloride; DI1K,3K)-1-Kbenzylmethylamino)-methyl|-33-methylcyclohexyl)-acetic acid hydrochloride or 70 (1K,3K)-3-methyl-1-methylaminomethylcyclohexyl)-acetic acid hydrochloride. 6. A method of treating diabetic retinopathy, which includes the stage of prescribing a therapeutically effective amount of a compound of formulas I, II and/or I to a patient in need thereof. NOS Yi sn i 21p SN Ge o 2 to Ge de ve g, s r, ek ' (o) ho 21 ti s K. E, i- Ki Ko III yuyu IS) ge Ez g; and E, them KE 5 in the nose "a and in o s (sn schi (spo, :z" 2 t Kk KE, 5 r ge p -I 12 v s Ki Z Go KE, 1 E Re c. in? -I 7 in Co) where: Ka is H, C4-Cio-alkyl, C3-Cio-cycloalkyl, in which from 17 to 3 carbon atoms may be replaced by a heteroatom selected from 0, 5 or ME, where B2 is hydrogen or C.-C:o-alkyl, substituted by C.4-Cio-alkyl containing a halogen, amine, C4-Cio-alkoxy group, C3-C.o-cycloalkyl or hydroxyl, allyl, Co-Cv-alkynyl, C4- C.4-Cio-alkanoyl, C.4-Cio-alkoxy-C4-Cio-alkanoyl, sulfonyl, phenyl; benzyl or F) C/-Ce-aryl-C4-Cio-alkyl, in which from 1 to 4 ring aryl atoms can be replaced by a heteroatom selected from O, 5 or M; moreover, the specified alkyl, alkoxyl, alkynyl, alkanoyl or allyl groups can be substituted preferably by 1-3 groups selected from the group that includes MAE "B, where KE" and KE? means hydrogen or C.-CiO-alkyl, unsubstituted or substituted phenyl, thio-Ci--Cv-alkyl, C.-Ci-Alkoxy, hydroxy, carboxy, C.-Ci-Alkoxycarbonyl, halogen, nitrile, C3- C10-cycloalkyl, and a 5- or b-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, which in turn may be substituted by C1-C8-alkyl or unsubstituted or substituted halogen (CH 2 ) rphenyl, where n means 1, 2 or 3, oxygen and sulfur; and wherein said cycloalkyl groups may be substituted with 65 hydroxy or keto groups, and said aryl, phenyl and benzyl groups may be substituted with 1, 2 or C groups selected from the list which includes C 4-Cio-alkyl optionally substituted as indicated above, C.-Cio-alkyl, optionally substituted as indicated above, a thio group, thio-C 4-Cio-alkyl, hydroxy, carbonyl, a group of the formula -MA"B5, T(СНо)тОВ" or Т(СНо)тСО» B, where t means from 1 to 6, T means O, 5, MA", CHOKU, ME"VZ or SV", CO means O, 5, MA?, WHAT) or MERE, where B and EZ are defined as described above, and 5 is unsubstituted or substituted as indicated above, C.4-C.o-alkyl, wherein n is an independent integer from 1 to 3; K.-Ka and K/0o-Ki34 are independently H, unsubstituted or substituted as indicated above, by C.i-Cio-alkyl; and X - MA 4, and if there is more than 1 stereoisomer, then each chiral center can independently be K or 5; or a pharmaceutically acceptable salt, ester or amide thereof. 7. Method according to item b, where t and n are 1; X is MK.4; Ka is H; Ku is methyl; K, and K5 is methyl; Ka is methyl; Co is methyl; K, and Ka is methyl; K, and Ka is methyl; K.-Ka and Kio-Kiz are H; Co is C-Cio-alkyl; Co is benzyl; Ka is C1-C10-alkyl; Ka is C1-C6-aryl-C4-C0-alkyl; Ka is C3-C40-cycloalkyl; K.-Ka is H; K.-Kav and Kio-K44 are H; K.-Co and K;-Ka are H or P" is methyl, and these groups may be substituted as described above. 8. The method according to claim 6, where Kz is Si-Si0-alkyl, K.4-Ko and K.-K44 and Ki4 are hydrogen, those n are 1, and X is MK.4; Kz and K44 are C1-C10-alkyl, K.-K» and Ku/-K.o and K.4 are hydrogen, t and n is 1, and X is MK.4; Kz and K./4 are C4-Cio-alkyl, K.-K»o and KA-Kuo and Kia are hydrogen, t and n is 1, Ko is C-C4o-alkyl, and X is MK.4; and K.4-K44 and K/4 are hydrogen, tip is 1, and X is O, wherein said groups may be substituted as described above. 9. The method according to claim 6, where the compound is selected from the group including: 1о5,38,5р8. "(1-aminomethyl-3,5-diethylcyclohexyl)-acetic acid hydrochloride; trans-"1Kk,ZKH (1-aminomethyl-3-methylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-2-methylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-3,3-dimethylcyclohexyl)-acetic acid hydrochloride; (1U-) (trans)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid hydrochloride; Ge (cis/trans)-(3K)-(1-aminomethyl-3-methylcyclopentyl)-acetic acid hydrochloride; o (U (trans)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid hydrochloride; (U (trans)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid hydrochloride; 155.38 58. "(1-aminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 1T1o,38.5r. -(3,5-dimethyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; c 1T1o,38.5rD. "(1 -ethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 155.98. 58 -(1-benzylaminomethyl)-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 155.38 58. dimethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; at 155,938.58. "(1-butylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 15.38 58. 41-Kbenzylmethylamino)-methyl)|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; m 1To,38,5y. -(3,5-dimethyl-1-methylaminomethylcyclohexyl)-acetic acid hydrochloride; 155.38. ,58. -1-(isobutylaminomethyl)-3,5-dimethylcyclohexyl)|-acetic acid hydrochloride; 11-(cyclobutylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 155.38 58 -I1-(isopropylaminomethyl)-3,5-dimethylcyclohexyl|)|-acetic acid hydrochloride; « 1-aminomethyl-1-cyclohexanoacetic acid; shshc 1-aminomethyl-1-cyclopentanoacetic acid; and 1-aminomethyl-1-cyclopentanoacetic acid sodium salt; "" 11-(2-methylbutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(4,4,4-trifluorobutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-ethylaminomethylcyclohexyl)-acetic acid hydrochloride; - and 11-Kcyclopropylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-K2-hydroxy-1-methylethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; ini (1-(isobutylaminomethyl|-cyclohexyl|-acetic acid hydrochloride; c (1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; P1-(isopropylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; Che (1-cyclohexylaminomethylcyclohexyl|-acetic acid hydrochloride; from P1-(benzylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; (1K,3K)-3-methyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(cyclopentylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11 -(cyclohexylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; P1-(tert-butoxycarbonylaminomethyl)-cyclohexyl| acetic acid; iF) (3K,55)-1-cyclobutylaminomethyl)-3,5-dimethylcyclohexyl|-acetic acid hydrochloride; ko u3K,55)-3,5-dimethyl-1-((2-methylbutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; T(3K,55)-1-K(2-hydroxy-1-methylethylamino)-methyl|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; in T(3K,55)-1-(2,2-dimethoxyethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; T(3K,55)-1-(cyclopentylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; T(3K,55)-1-Kcyclohexylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-cyclohexylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (1-dimethylaminomethylcyclohexyl)-acetic acid hydrochloride; 65 (1-butylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(2,2-dimethoxyethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (1-methylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(benzylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-CZ-phenylpropylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-ethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-4-ethylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-4-propylcyclohexyl)-acetic acid hydrochloride or (ZK,55)-3,5-dimethyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride. 10. The method of inhibiting aminotransferases dependent on amino acids with a branched chain in patients 7/0 who have this need, which includes the stage of prescribing a therapeutically effective amount of a compound of formulas I, II and/or g nos about KE to Ge de ve g, Be-. BUT сх й-к у Ж (8) 21 t s E E 11 1 m Ki Ko ЙИ ИС) E E В Z yu Kk; Kk, Hn v. KE 5 eE nos ' y y « / (SN), shi s (SN . ;" E KE, 13 v e 2 I 12 E - shcha Z s b r uev, t 7 v -i de: Kz Ka is H, C4-Cio-alkyl, C3-Cio-cycloalkyl, in which from 17 to 3 atoms carbon can be replaced by a heteroatom selected from 0, 5 or ME, where B? means hydrogen or C.-C.o-alkyl substituted by C.-C.o-alkyl containing a halogen, amine, C.4-C.o.-alkoxy group, C.3-C.o-cycloalkyl or hydroxyl, allyl, B Co-C.-alkynyl , C.-Cio-alkanoyl, C.4-C-Alkoxy-C1-Cio-alkanoyl, sulfonyl, phenyl, benzyl or C.-Ce-aryl-C4-Cio-alkyl, in which from 1 to 4 ring aryl atoms can be replaced by a heteroatom, (F) selected from O, 5 or M; moreover, the specified alkyl, alkoxyl, alkynyl, alkanoyl or allyl groups can be substituted, preferably by 1-3 groups selected from the group that includes ME"B?, where B" and KU. means hydrogen or C.i-Cio-alkyl, unsubstituted or substituted phenyl, thio-C.--Cv-alkyl, C.--Ci-alkyl, hydroxy, bo carboxy, C.i.-Ci-Alkoxycarbonyl, halogen, nitrile . -alkyl or unsubstituted or substituted halogen (CHNo)rphenyl, where n means 1, 2 or C, oxygen and sulfur; and wherein said cycloalkyl groups may be substituted with hydroxy or keto groups, and said aryl, phenyl and benzyl groups may be substituted with 1, 2 or C 65 groups selected from the list including C 1 -C 10 alkyl optionally substituted as indicated above, C1-C0-alkyl, optionally substituted as above, thio-group, thio-C 4-C4o-alkyl, hydroxy, carbonyl, a group of the formula -ME"B?, Т(СНо)тОВ" or Т(СНо)птСО»Б, where t means от 1 to 6, T means О, 5, ME", ЧО, MA" or СВ"Б", O is O, 5, MAR, CHO)? or MERE, where B" and 2 are as defined above, and K 5 is unsubstituted or substituted as above, C.4-C.o-alkyl; t Y n is an independent integer from 1 to 3; C.-Cav and C.sub.1-C.sub.4 are independently H, unsubstituted or substituted as indicated above, C.-Cio-alkyl; and xX - MA 4, and if there is more than one stereoisomer, each chiral center can independently be K or 5; or a pharmaceutically acceptable salt, ester or amide thereof. 70 11. The method according to claim 10, where those n are 1; X is MK.4; Ko is H; K. is methyl; K, and Kv are methyl; Ka is methyl; Co is methyl; K, and Ka is methyl; K,; and Ka is methyl; K.-Ka and K/o-Kiz are H; Co is alkyl; Co is benzyl; K44 is C1-C10-alkyl; Ka is C1-C6-aryl-C4-C0-alkyl; Ka is C3-C40-cycloalkyl; K.-Ka is H; K.-Kav and Kio-K44 are H; K.-Co and K;-Ka are H or P" is methyl, and these groups may be substituted as indicated above. 12. The method according to claim 10, where Kz is alkyl, K.-Ko and K.-K.4 and Ki is hydrogen, such that 1, axX is MK; There are Kz and Kch41 175. C.4-Sio-alkyl, K.-K»o and K.A-Kcio and K/d4 are hydrogen, those n are 1, and X is MK.4; Kz and K.44 are alkyl, K.4-K»o and KA-Kio and Kia. is hydrogen, t and n are 1, Ka is C4-Cio-alkyl, and X is MK.4; and K.-K.44 and K/4 are hydrogen, T is 1, and X is O, wherein said groups may be substituted as indicated above. 13. The method according to claim 10, where the compounds are selected from the group that includes: trans-"1Kk,ZKKH (1-aminomethyl-3-methylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-2-methylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-3,3-dimethylcyclohexyl)-acetic acid hydrochloride; (1U-) (trans)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid hydrochloride; (cis/trans)-(3K)-(1-aminomethyl-3-methylcyclopentyl)-acetic acid hydrochloride; (U (trans)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid hydrochloride; c (U (trans)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid hydrochloride; o 155.38 58 "(1-aminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 1T1o,38.5r. -(3,5-dimethyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; 1T1o,38.5rD. "(1 -ethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 155.98. -3,5-dimethylcyclohexyl)-acetic acid hydrochloride; che 155,938.,58. "(1-butylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; 15.38 58. 41-Kbenzylmethylamino)-methyl)|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; at 1 To, 38, 5 years. -(3,5-dimethyl-1-methylaminomethylcyclohexyl)-acetic acid hydrochloride; Io) 155.38. ,58. -1-(isobutylaminomethyl)-3,5-dimethylcyclohexyl)|-acetic acid hydrochloride; M 11-(cyclobutylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 155.38 58 -I1-(isopropylaminomethyl)-3,5-dimethylcyclohexyl|)|-acetic acid hydrochloride; 1-aminomethyl-1-cyclohexanoacetic acid; 1-aminomethyl-1-cyclopentanoacetic acid; 1-aminomethyl-1-cyclopentanoacetic acid sodium salt; with c 11-(2-methylbutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-(4,4,4-trifluorobutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; ;" (1-ethylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-Kcyclopropylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 11-K2-hydroxy-1-methylethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; -I (1-(isobutylaminomethyl|-cyclohexyl|-acetic acid hydrochloride; (1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; o P1-(isopropylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; c (1-cyclohexylaminomethylcyclohexyl|-acetic acid hydrochloride) ; P1-(benzylaminomethyl)-cyclohexyl|-acetic acid hydrochloride; Ш-(1К,3К)-3-methyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride; He 11-(cyclopentylmethylamino)-methyl|-cyclohexyl)-acetic acid 11-(cyclohexylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; P1-(tert-butoxycarbonylaminomethyl)-cyclohexyl| acetic acid; (3K,5)-1-cyclobutylaminomethyl)-3,5-dimethylcyclohexyl|-acetic acid hydrochloride; u3K,55)-3,5-dimethyl-1-((2-methylbutylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; F) T(3K,55)-1-K(2-hydroxy-1-methylethylamino)-methyl|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; ka T(3K,55)-1-(2,2-dimethoxyethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; T(3K,55)-1-(cyclopentylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; in T(3K,55)-1-Kcyclohexylmethylamino)-methyl/|-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-cyclohexylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (1-dimethylaminomethylcyclohexyl)-acetic acid hydrochloride; (1-butylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(2,2-dimethoxyethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; 65 (1-methylaminomethylcyclohexyl)-acetic acid hydrochloride; 11-(benzylmethylamino)-methyl|-cyclohexyl)-acetic acid hydrochloride; (ZK,55)-1-ethylaminomethyl-3,5-dimethylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-4-ethylcyclohexyl)-acetic acid hydrochloride; (1-aminomethyl-4-propylcyclohexyl)-acetic acid hydrochloride or (ZK,55)-3,5-dimethyl-1-propylaminomethylcyclohexyl)-acetic acid hydrochloride. 14. A method of treating neurological disorders, depression, anxiety, panic, mania, bipolar disorders, inflammatory diseases, glaucoma, pain, or gastrointestinal disorders, which includes the step of administering a therapeutically effective amount of a compound of formula IM to a patient in need thereof, Ko, ' o x son 7 v e 4 1 KE. B. where: K.-K. is hydrogen or C.-C.o-alkyl; X is ME; K5 is hydrogen or C.-C.o-alkyl, Kv is C.-C.io-alkyl, benzyl, C/-Ce-aryl-C4-Cio-alkyl, in which from 1 to 4 ring aryl atoms may be replaced by a heteroatom , selected from O, 5 or M, C, 4-Cio-alkyl, C3-Cio-cycloalkyl, in which from 1 to 3 carbon atoms can be replaced by a heteroatom selected from 0, 5 or ME, where K2 means o hydrogen or C1-C10-alkyl, allyl, C4-C10-alkyl-C3-C10-cycloalkyl, in which from 1 to 3 cycloalkyl ring atoms can be replaced by a heteroatom selected from 0, 5 or MK, where B? has the above value, trisubstituted halogen-C41-Cio-alkyl, and the indicated alkyl, alkyl, allyl groups can be substituted, preferably by 1-3 groups selected from the group that includes ME "E?, where B" and KE? mean hydrogen or s C.-Co-alkyl, unsubstituted or substituted phenyl, thio-C.-Cv-alkyl, C.i-Cv-alkoxy, hydroxy, carboxy, M C 1 -C 6 -Alkoxycarbonyl, halogen, nitrile, C 3 -C 10 -cycloalkyl, and a 5- or b-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, which in turn , о may be substituted by C.1-Cv-alkyl or unsubstituted or substituted by halogen (CH0) phenyl, where n means T1, 2 or 3, oxygen and sulfur; and the specified cycloalkyl groups may be substituted by a hydroxy group or a C 2 keto group, and the specified aryl and benzyl groups may be substituted by 1, 2 or 3 groups selected from the list including C 1 -C 10 -alkyl optionally substituted as indicated above, C4-C4o-alukoxyl, optionally substituted as indicated above, a thio group, thio-C 4-C-o-alkyl, hydroxy, carbonyl, a group of the formula -MA"B?, T(СНо)тОВ" or T (СНо)тСО»В, where т means from 1 to 6, T means О, 5, ME", MOЖ", MA"? or СВ", O means О, 5, ME, « 20 MOЖ or MARK, where В " and 5 are as defined above, and B? means unsubstituted or substituted as 73 with above, C4-C-o-alkyl; and if K./-Ku is each hydrogen, then Ke is not methyl; or a pharmaceutically acceptable salt, ester or amide thereof. . and? -i 1 1 -i Ko) ime) 60 b5